Paxerol™ for Treatment of Nocturia - A Phase II Placebo-Controlled Trial
Condition: Nocturia
MeSH terms: Nocturia
Intervention: Placebo; Paxerol - Dose Level 1; Paxerol - Dose Level 2; Paxerol - Dose Level 3
Intervention description: Subjects are treated with Placebo tablets; Subjects are treated with the first dose level of Paxerol; Subjects are treated with the second dose level of Paxerol; Subjects are treated with the third dose level of Paxerol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 86.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a multi-center, double-blind, placebo-controlled study with two weeks of daily oral
      administration of one of three dose levels of Paxerol or placebo in subjects with nocturia.
      Eligible study subjects will be identified according to inclusion/exclusion criteria (see
      below), and baseline assessments will be recorded.

      Due to small sample size of 25 patients per group in this proof-of-principle dosing-finding
      trial, stratification according to gender and BMI will be difficult. However, similar
      distribution of patient types to the four treatment groups will be attempted by evenly
      assigning patients to the four treatment groups according to genders and body mass index
      (BMI) of <25, 25-30 and 30-40.

      Paxerol or placebo will be taken 30 minutes before bedtime daily for two weeks. Nocturia
      frequency, Nocturia Quality of Life (NQOL), Duration of First Undisturbed Sleep (DFUS), total
      hours of nightly sleep, safety and tolerability will be monitored before and after a two-week
      treatment period. Results from subjects treated with different doses of Paxerol and placebo
      will be assessed and compared. Baseline urinary Prostaglandin E2 (PGE2) production will also
      be assayed to assess potential correlation between baseline urinary PGE2 production and
      responsiveness to Paxerol treatment.
    

Eligibility criteria:

        Inclusion:

          -  Subjects diagnosed with nocturia, as defined by International Continence Society
             (i.e., the interruption of sleep one or more times at night to void), confirmed by
             evaluation in participating investigator's urology practice for the following
             characteristics: nocturia is related to overactive bladder (OAB); nightly ≥2.5 times
             nocturia present for at least 3 months and not considered caused by persistent or
             recurrent urinary tract infection; Post-Void Residual (PVR) urine volume must be <80
             cc at the time of screening; did not respond well to, or unwilling to have, lifestyle
             modification, behavioral and conservative therapies, such as dietary changes, timed
             voiding, urge suppression (e.g., pelvic floor exercises [PFE] at the time of urge
             episodes), biofeedback, etc.

          -  Males or females, ≥18 years of age with Body Mass Index (BMI) <40.

          -  Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
             sterile) must use accepted contraceptive methods (abstinence, intrauterine device
             [IUD], oral contraceptive or double barrier device) during the study, and must have a
             negative serum or urine pregnancy test within 1 week prior to treatment initiation.

          -  Ability to understand and sign the study Informed Consent Form (ICF), communicate with
             the investigators, and understand and comply with the requirements of the protocol,
             including completion of participation in all phases of the study.

          -  No current or medical history of gastrointestinal bleeding or malformation; bleeding
             diathesis; or restless leg syndrome.

          -  Not using within 4 weeks before study initiation, or anticipating the use during the
             study, of the following drugs: antiplatelet or anticoagulant drugs; any Selective
             Serotonin Re-uptake Inhibitors (SSRIs) or anti-diuretic medications; or warfarin

          -  Resting heart rate between 55 and 100 beats per minute, inclusive of both.

        Exclusion:

          -  Pregnant or nursing women.

          -  Known presence of urinary tract infection (UTI) within 4 weeks before study initiation

          -  Known sleep interruptions due to sleep apnea, dyspepsia or other gastro-intestinal
             symptoms, seizure disorders or other neurologic symptoms

          -  Allergy to or intolerance of acetaminophen, ibuprofen, or any inactive component of
             the study drug formulations.

          -  A history of allergy to aspirin or other NSAIDs.

          -  Congenital or acquired structural abnormality of the genitourinary tract.

          -  Prostate cancer of any stage that has required any treatment.

          -  Any neurodegenerative disease (including but not limited to Parkinson's Disease,
             Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Pick's Disease, Multi-Infarct
             Dementia or recent history of head trauma associated with concussion, stroke or
             serious cerebrovascular events) which may indicate problems in providing consistent
             and reliable Patient-Reported Outcomes (PRO) such as diary, Quality-of-Life, etc.
             required in this study.

          -  Uncontrolled hypertension (blood pressure >150/100 mm Hg).

          -  Serious medical illness, such as significant cardiac disease (e.g. symptomatic
             congestive heart failure, unstable angina pectoris, myocardial infarction within the
             past 6 months, uncontrolled cardiac arrhythmia, or New York Heart Association Class
             II, III or IV), severe debilitating pulmonary disease, or history of stroke
             (hemorrhagic or thrombotic), A-V malformation, or other cerebrovascular disease.

          -  Receipt of any investigational drug or participation in any clinical trial within 30
             days prior to study participation.

          -  Use of acetaminophen, ibuprofen, acetylsalicylic acid (ASA) or any NSAID on the day of
             entry into the study or any anticipated use during the study. In the event of the need
             for any unanticipated use of such drugs during the trial, the timing and doses of such
             use should be carefully recorded and reported at the next visit to the clinic.

          -  Any medical problem requiring uninterrupted use of acetaminophen, ibuprofen, or any
             NSAIDs, or any other pain medication.

          -  Daily use of phosphodiesterase (PDE) inhibitors (such as sildenafil, tadalafil,
             vardenafil, avanafil, and udenafil) within 30 days prior to study or any anticipated
             daily use during the study. (Note: PDE inhibitors are known to have positive effect on
             voiding dysfunction and thus can interfere with the assessment of Paxerol [Ückert et
             al 2010].)

          -  History of polyuria or evidence of polyuria (estimation of daily production >2.5
             liters of urine).

          -  Uncontrolled Type 1 or 2 diabetes mellitus (HbA1c >7.0%).

          -  Diabetes insipidus.

          -  Significantly impaired renal function (creatinine clearance <50 mL/min/1.73kg/m2)

          -  Any visual, motor or other sensory abnormality that might predispose to a fall on
             nocturnal arising to urinate.

          -  Evidence of hyponatremia at baseline.

          -  Any significant disease or abnormality of the neurological, visual, gastrointestinal,
             hepatobiliary, pulmonary, cardiovascular, genitourinary or musculoskeletal system
             other than those specified above that, in the opinion of the involved investigator,
             might compromise the ability of the prospective subject to participate in the study or
             that could confound interpretation of study results.

          -  Any abnormality on screening medical history, physical examination or clinical
             laboratory examination other than those specified above that, in the opinion of the
             involved investigator, might confound interpretation of study results.

          -  Subjects with known hepatitis, HIV-AIDS, or tuberculosis.

          -  Subjects with known dysrhythmia of any form.