| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Uncomplicated recurrent urinary tract infections |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038140 |
| E.1.2 | Term | Recurrent urinary tract infection |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary efficacy evaluation will be time to first recurrence of a qualifying UTI (i.e., at least one of the following symptoms persisting for at least one day: dysuria, increased frequency, increased urgency, or suprapubic pain; and bacterial count of ≥10^3 CFU/mL of at least one species) between the two active arms (pooled) versus placebo. The primary evaluation will be supported by pairwise comparisons among the three treatment groups. |
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| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives include:
• Rate of UTI cases
• Rate of UTI cases categorized by the following at baseline: number of qualifying historical UTIs, previous use of Uro-Vaxom®, and menopausal status
• Rates of UTI cases by study period (treatment period versus follow-up period)
• Impact of using an alternative bacterial count definition of a UTI; ≥10^3 versus ≥10^5 CFU/mL
• Effect of anti-infective use on UTI rate
• Bacterial distribution of E. coli and non-E. coli infections
• Exploratory evaluation of relationship between rate of UTIs and:
- Lewis phenotype;
- Periurethral/introital gram-negative bacterial colonization;
- Intravaginal/urinary sIgA levels;
- Serum IgA, IgE, IgG, and IgM levels;
- B- and T-lymphocyte levels; and
- Cytokine release profile of PBMCs;
As well as the incidence of bacteriuria.
Secondary safety objectives include:
• Physical examinations
• Vital signs
• Laboratory tests
• Adverse events and serious adverse events |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient must meet the following criteria at Screening (Visit 1) to participate in this study:
I.1 Ambulatory female aged 18 to 73 years
I.2 Acute uncomplicated UTI at Screening, including at least one of the following symptoms persisting for at least one day: dysuria, increased frequency, increased urgency, or suprapubic pain
I.3 If of child-bearing potential, must agree to use an adequate, consistent form of contraception during the study [e.g., oral contraceptives or hormone-containing intra-uterine device use during the study at the same dose and regimen and for at least 90 days prior to study start; abstinence, sterilization of self or partner, or any other contraceptive method(s) not prohibited by the protocol with a Pearl index < 1 (a Pearl index of 1 corresponds to 1 woman out of 100 women becoming pregnant within 1 year using the same method of contraception)]
I.4 Written informed consent
A patient must also meet the following additional criteria at Randomization (Day 0/Visit 2) to participate in this study:
I.5 Acute uncomplicated UTI at Screening must have included a clean-catch midstream bacterial count of ≥10^3 CFU/mL of at least one species
I.6 History of recurrent UTI:
a. For patients not requiring a Qualification Period: 3 qualifying, documented UTIs in the year prior to Randomization (Day 0) OR
b. For patients requiring a Qualification Period: 2 qualifying, documented UTIs in the 120 days prior to Randomization (Day 0)
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| E.4 | Principal exclusion criteria |
A patient will be excluded from participating in the study at Screening (Visit 1) and unless noted otherwise, Randomization (Day 0/Visit 2) for any of the following reasons:
E.1 History of more than 10 UTIs in the year before Screening meeting the documented historical UTI definition
E.2 Long-term (>30 days continuous therapy) or frequent intermittent (>14 days/month for a non-UTI indication) anti-infective use in the 90 days before Screening
E.3 History of interstitial cystitis, inflammatory bowel disease, or chronic enteropathies
E.4 Functional and structural abnormalities within the urinary tract or obstructive morphological changes as documented in the patient’s medical history
E.5 History of persistent UTIs (i.e., history of at least 2 UTIs meeting the documented historical UTI definition lasting ≥ 14 days in the year prior to Screening)
E.6 Use of a urinary catheter within 90 days prior to Screening, however, transient (“in and out”) catheterization by a qualified medical professional using accepted catheterization techniques (i.e., perineal preparation) for the purposes of collection of an adequate bladder sample is acceptable
E.7 Known symptoms of neurogenic bladder dysfunction, as manifested either by the presence of a neurological condition (e.g., spinal cord injury) that is associated with neurogenic bladder dysfunction or known abdominal urodynamic studies (voiding cystourethrogram, cystometry) consistent with the diagnosis of neurogenic bladder dysfunction
E.8 Abnormal clinically significant laboratory values, as determined by the investigator, at Screening
E.9 Severe cardiovascular disease (e.g., left ventricular failure, stroke)
E.10 Significant liver insufficiency — i.e., AST and ALT > 2xULN
E.11 Renal disease, pyelonephritis, or significant renal insufficiency (i.e., serum creatinine > 1.5 mg/dL [133 µmol/L])
E.12 Malignant disease within 5 years of entering the study (excluding basal cell carcinoma of the skin, carcinoma in situ of the uterine cervix treated with cryosurgery or conization, or isolated cutaneous melanomas <5 mm in the longest diameter)
E.13 Active autoimmune disease and other systemic diseases related to immune system disorders (except diabetes mellitus with controlled blood glucose levels during the 90 days prior to Screening, as determined by the investigator)
E.14 Pregnant, lactating, or planning to become pregnant
E.15 Unreliable or non-compliant, including patients with known history of alcoholism, drug abuse, or serious psychiatric disorder; as well as patients unwilling to abide by the requirements of the protocol
E.16 Major surgical procedure, registered pharmaceutical immunomodulatory therapy for indications other than UTI, use of any experimental drug or device, or participation in another clinical trial within the 90 days prior to Screening
E.17 Exposure to any registered pharmaceutical immunomodulatory therapy for UTI [e.g., Uro-Vaxom® (also known as OM-89/OM-89S/AP-89) or StroVac®] or Subreum® within 1 year prior to Screening
E.18 Anticipated antibiotic use during the study, except for the treatment of acute UTI
E.19 Use of hormone replacement therapy or cranberry products for less than the 90 days prior to Screening. [Use of these products is allowed IF the dose and regimen remain constant at least 90 days before Screening and for the duration of the study.]
E.20 Any condition, as determined by the investigator, that would interfere with the patient’s ability to comply with study instructions, might confound the interpretation of the study results, or put the patient at risk
E.21 Personnel, or relative of personnel of, the sponsor (Alita), CRO (CRM), or the investigative sites
A patient will be excluded from participating in the study at Randomization (Day 0/Visit 2) for any of the following reasons:
E.22 Known or suspected UTI at Day 0
E.23 Oral temperature >38.0°C at Day 0
E.24 Abnormal clinically significant laboratory values, as determined by the investigator, at Day 0
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy analysis will be based upon the time to first recurrence of a qualifying UTI (i.e., at least one of the following symptoms persisting for at least one day: dysuria, increased frequency, increased urgency, or suprapubic pain; and bacterial count of ≥10^3 CFU/mL of at least one species) between the two active arms (pooled) versus placebo. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 100 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The stopping rule for safety includes any AE trends or SAEs that are indicative of a substantial risk for the patient at any time during the study.
If the study is not terminated early based upon safety concerns, the study will continue until the last patient has reached at least Visit 8 (Day 180) and approximately 220 patients have experienced a UTI qualifying as a primary endpoint; the data will be analyzed at the 0.15 level of significance.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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