Oral Omadacycline vs. Oral Nitrofurantoin for the Treatment of Cystitis

• ClinicalTrials.gov Identifier: NCT03425396
• Recruitment Status: Completed
• First Posted: February 7, 2018
• Results First Posted: June 4, 2020
• Last Update Posted: June 9, 2020
• Sponsor: Paratek Pharmaceuticals Inc
• Information provided by (Responsible Party): Paratek Pharmaceuticals Inc

Tracking Information

• First Submitted Date: December 28, 2017
• First Posted Date: February 7, 2018
• Results First Submitted Date: May 15, 2020
• Results First Posted Date: June 4, 2020
• Last Update Posted Date: June 9, 2020
• Actual Study Start Date: January 4, 2018
• Actual Primary Completion Date: May 15, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2020)

Number of Participants With an Investigator Assessment of Clinical Response at the Post Therapy Evaluation (PTE) Visit (ITT Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 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 sufficient resolution of cystitis signs and symptoms at the PTE visit such that no additional systemic antimicrobial therapy was 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. The clinical outcome was deemed as Indeterminate when the PTE visit was not completed.

Original Primary Outcome Measures (submitted: February 6, 2018)

• Investigator's assessment of clinical response at Post Treatment Evaluation (PTE) based on microbiological response. [ Time Frame: 14 days ]
  Clinical success is defined as sufficient resolution of cystitis 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 14-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 UTI signs and symptoms. [ Time Frame: 14 days ]
  Each subject will record her assessment of UTI signs and symptoms severity using the UTI Symptoms Assessment questionnaire (UTISA) during each visit. The UTISA is a 14-item instrument asking about the severity and bothersomeness of seven key uUTI symptoms, and applies a 4-point scale: No Symptoms, Mild, Moderate, Severe. The investigator will review each subject's responses and decide at the end of their treatment if there is sufficient resolution of UTI 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: 14 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 14-day time frame.

Current Secondary Outcome Measures (submitted: May 15, 2020)

• Number of Participants With an Investigator Assessment of Clinical Response at the End of Treatment (EOT) Visit (ITT Population) [ Time Frame: EOT visit (within 1 to 2 days following the last dose of study drug i.e. up to approximately 9 days) ]
  Clinical response was determined by the investigator at the EOT visit by assessing whether or not the participant met the clinical outcome of Clinical Success, Clinical Failure. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the EOT visit such that no additional systemic antimicrobial therapy was required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection at the EOT visit such that use of additional systemic antimicrobial therapy for the current infection was required. The clinical outcome was deemed as Indeterminate when the EOT visit was not completed.
• Number of Participants With an Investigator Assessment of Clinical Response at the EOT Visit (Microbiological [Micro]-ITT Population) [ Time Frame: EOT visit (within 1 to 2 days following the last dose of study drug i.e. up to approximately 9 days) ]
  Clinical response was determined by the investigator at the EOT visit by assessing whether or not the participant met the clinical outcome of Clinical Success, Clinical Failure, or Indeterminate. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the EOT visit such that no additional systemic antimicrobial therapy was required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection at the EOT visit such that use of additional systemic antimicrobial therapy for the current infection was required. The clinical outcome was deemed as Indeterminate when the EOT visit was not completed.
• Number of Participants With an Investigator Assessment of Clinical Response at the EOT Visit (CE-EOT Population) [ Time Frame: EOT visit (within 1 to 2 days following the last dose of study drug i.e. up to approximately 9 days) ]
  Clinical response was determined by the investigator at the EOT visit by assessing whether or not the participant met the clinical outcome of Clinical Success or Clinical Failure. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the EOT visit such that no additional systemic antimicrobial therapy was required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection at the EOT visit such that use of additional systemic antimicrobial therapy for the current infection was required. For the CE population, the clinical outcome was not deemed as indeterminate response.
• Number of Participants With an Investigator Assessment of Clinical Response at the PTE Visit (CE-PTE Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 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 or Clinical Failure. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the PTE visit such that no additional systemic antimicrobial therapy was 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. For the CE population, the clinical outcome was not deemed as indeterminate response.
• Number of Participants With an Investigator Assessment of Clinical Response at the PTE Visit (Micro-ITT Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 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 sufficient resolution of cystitis signs and symptoms at the PTE visit such that no additional systemic antimicrobial therapy was 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. The clinical outcome was deemed as Indeterminate when the PTE visit was not completed.
• Number of Participants With an Investigator Assessment of Clinical Response at the Final Follow-up (FFU) Visit (ITT Population) [ Time Frame: FFU visit (A FFU occurred 30 to 37 days following the first dose of study drug) ]
  Clinical response was determined by the investigator at the FFU visit by assessing whether or not the participant met the clinical outcome of Clinical Success, Clinical Failure, or Indeterminate. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the FFU visit such that no additional systemic antimicrobial therapy was required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection at the FFU visit such that use of additional systemic antimicrobial therapy for the current infection was required. The clinical outcome was deemed as Indeterminate when the FFU visit was not completed
• Number of Participants With an Investigator Assessment of Clinical Response at the FFU Visit (CE-FFU Population) [ Time Frame: FFU visit (A FFU occurred 30 to 37 days following the first dose of study drug) ]
  Clinical response was determined by the investigator at the FFU visit by assessing whether or not the participant met the clinical outcome of Clinical Success or Clinical Failure. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the FFU visit such that no additional systemic antimicrobial therapy was required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection at the FFU visit such that use of additional systemic antimicrobial therapy for the current infection was required. For the CE population, the clinical outcome was not deemed as indeterminate response.
• Number of Participants With an Investigator Assessment of Clinical Response at the FFU Visit (Micro-ITT Population) [ Time Frame: FFU visit (A FFU occurred 30 to 37 days following the first dose of study drug) ]
  Clinical response was determined by the investigator at the FFU visit by assessing whether or not the participant met the clinical outcome of Clinical Success, Clinical Failure, or Indeterminate. Clinical Success was defined as sufficient resolution of cystitis signs and symptoms at the FFU visit such that no additional systemic antimicrobial therapy was required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection at the FFU visit such that use of additional systemic antimicrobial therapy for the current infection was required. The clinical outcome was deemed as Indeterminate when the FFU visit was not completed.
• Number of Participants With a Microbiological Response at the EOT Visit (Micro-ITT Population) [ Time Frame: EOT visit (within 1 to 2 days following the last dose of study drug i.e. up to approximately 9 days) ]
  Microbiological response was determined programmatically at the EOT visit by assessing whether or not the participant met the microbiological outcome of Favorable, Unfavorable, or Indeterminate. Favorable microbiological outcomes included eradication and presumed eradication i.e., urine specimen showed absence of the original baseline pathogen or the baseline pathogen grew at <10^4 CFU/mL at visit. Unfavorable microbiological outcome included persistence i.e. urine culture showed continued presence (defined as ≥10^4 CFU/mL) of the original baseline pathogen(s) at visit. The microbiological outcome was deemed as Indeterminate when the urine specimen was not available to culture or the culture result was not interpretable.
• Number of Participants With a Microbiological Response at the EOT Visit (ME-EOT Population) [ Time Frame: EOT visit (within 1 to 2 days following the last dose of study drug i.e. up to approximately 9 days) ]
  Microbiological response was determined programmatically at the EOT visit by assessing whether or not the participant met the microbiological outcome of Favorable or Unfavorable. Favorable microbiological outcomes included eradication and presumed eradication i.e., urine specimen showed absence of the original baseline pathogen or the baseline pathogen grew at <10^4 CFU/mL at visit. Unfavorable microbiological outcome included persistence i.e. urine culture showed continued presence (defined as ≥10^4 CFU/mL) of the original baseline pathogen(s) at visit. For the ME population, the microbiological outcome was not deemed as indeterminate response.
• Number of Participants With a Microbiological Response at the PTE Visit (Micro-ITT Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 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 Favorable, Unfavorable, or Indeterminate. Favorable microbiological outcomes included eradication and presumed eradication i.e., urine specimen showed absence of the original baseline pathogen or the baseline pathogen grew at <10^4 CFU/mL at visit. Unfavorable microbiological outcome included persistence i.e. urine culture showed continued presence (defined as ≥10^4 CFU/mL) of the original baseline pathogen(s) at visit. The microbiological outcome was deemed as Indeterminate when the urine specimen was not available to culture or the culture result was not interpretable.
• Number of Participants With a Microbiological Response at the PTE Visit (ME-PTE Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 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 Favorable or Unfavorable. Favorable microbiological outcomes included eradication and presumed eradication i.e., urine specimen showed absence of the original baseline pathogen or the baseline pathogen grew at <10^4 CFU/mL at visit. Unfavorable microbiological outcome included persistence i.e. urine culture showed continued presence (defined as ≥10^4 CFU/mL) of the original baseline pathogen(s) at visit. For the ME population, the microbiological outcome was not deemed as indeterminate response.

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: May 15, 2020)

• Number of Participants With Resolution of All Urinary Tract Infection (UTI) Signs and Clinical Symptoms at PTE Visit (ITT Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 2 days after the participant's first dose of study drug) ]
  Participants recorded their assessments using the UTI Symptoms Assessment (UTISA) questionnaire, a 14-item questionnaire that assessed the levels of 'severity' and 'bothersomeness' for seven UTI signs and symptoms: Frequency, Urgency, Pain/burning on urination, Incomplete voiding, Pain in pelvic area, Low back pain, and Blood in urine. 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 7 items, divided by the number of non-missing items, and then multiplied by 7. For each sub-scale, the total score ranged from 0 (least Severe/ least bothersome) and 21 (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 UTI Signs and Clinical Symptoms at PTE Visit (ITT Population) [ Time Frame: Day 14 (A PTE occurred on Day 14 ± 2 days after the participant's first dose of study drug) ]
  Participants recorded their assessments using the UTI Symptoms Assessment (UTISA) questionnaire, a 14-item questionnaire that assessed the levels of 'severity' and 'bothersomeness' for seven UTI signs and symptoms: Frequency, Urgency, Pain/burning on urination, Incomplete voiding, Pain in pelvic area, Low back pain, and Blood in urine. 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 7 items, divided by the number of non-missing items, and then multiplied by 7. For each sub-scale, the total score ranged from 0 (least Severe/ least bothersome) and 21 (worst severity/most bothersome). Number of participants with no worsening and absence of new UTI signs and clinical symptoms is reported. No worsening meant that each question score is same or better at post baseline.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oral Omadacycline vs. Oral Nitrofurantoin for the Treatment of Cystitis
• Official Title: A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the Safety and Efficacy of Oral Omadacycline and Oral Nitrofurantoin in the Treatment of Female Adults With Cystitis
• Brief Summary: The purpose of this study is to evaluate the safety and efficacy of oral omadacycline as compared to oral nitrofurantoin in the treatment of female adults with cystitis.
• Detailed Description: Participants were randomized to receive 7 days of treatment of either omadacycline or nitrofurantoin. The End of Treatment visit, Post Therapy Evaluation visit, and Final Follow-up visit was planned within 2 days following the last dose of study drug, on Day 14 (+/- 2 days) after the first dose of study drug, and within 30 to 37 days following the first dose of study drug, respectively. The study followed a double-dummy design. To maintain the study blinding, participants assigned to omadacycline received active omadacycline tablets and over-encapsulated nitrofurantoin placebo tablets. Participants assigned to the nitrofurantoin arm received omadacycline placebo tablets and over-encapsulated active nitrofurantoin capsules.
• 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

• Uncomplicated Urinary Tract Infection
• Cystitis

Intervention

• Drug: Omadacycline tablets
  Oral Omadacycline
• Drug: Nitrofurantoin capsules
  Oral Nitrofurantoin

Study Arms

• Experimental: Omadacycline 300/300 once every 24 hours
  Participants received omadacycline 300 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 300 milligrams orally, once every 24 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal.
  Intervention: Drug: Omadacycline tablets
• Experimental: Omadacycline 450/300 once every 24 hours
  Participants received omadacycline 450 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 300 milligrams orally, once every 24 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal.
  Intervention: Drug: Omadacycline tablets
• Experimental: Omadacycline 450/450 once every 24 hours
  Participants received omadacycline 450 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 450 milligrams orally, once every 24 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal.
  Intervention: Drug: Omadacycline tablets
• Experimental: Omadacycline 450/450 once every 12 hours
  Participants received omadacycline 450 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 450 milligrams orally, once every 12 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal.
  Intervention: Drug: Omadacycline tablets
• Active Comparator: Nitrofurantoin 100/100 once every 12 hours
  Participants received nitrofurantoin 100 milligrams orally, once every 12 hours, fed on Day 1 and nitrofurantoin 100 milligrams orally, once every 12 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal.
  Intervention: Drug: Nitrofurantoin capsules

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 8, 2019): 225
• Original Estimated Enrollment (submitted: February 6, 2018): 200
• Actual Study Completion Date: June 5, 2019
• Actual Primary Completion Date: May 15, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Female participants, age 18 or older who have signed the informed consent form
• Must have a qualifying uncomplicated urinary tract infection
• 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

Exclusion Criteria:

• Males
• Evidence of complicated urinary tract infection (UTI), upper UTI, vaginitis, or sexually transmitted infection
• Evidence of significant immunological disease
• Has received an investigational drug within the past 30 days
• Participants who are pregnant or nursing

Sex/Gender

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

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03425396
• Other Study ID Numbers: PTK0796-UUTI-17201
• 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: June 2020