Hyalofemme is a cream/gel containing hyaluronic acid, designed to be applied vaginally. This is primarily used in treatment of atrophic vaginitis and is applied by the patient once every three days. We intend treatment to continue for 6 months.

Ialuril is a bladder instillation designed to be delivered to the bladder via catheter. This is primarily used in patients suffering from recurrent UTI and acts to help rebuild the lining of the bladder, reducing irritation. Ialuril is applied weekly for 6 weeks, followed by every 2 weeks for 6 weeks, then once monthly for maintenance. Treatment will be continued for 6 months.

Atrophic Vaginitis

Urinary Tract Infections

Gel made with hyaluronic acid to be applied vaginally to treat atrophic vaginitis.

Hyalofemme

Bladder instillation of hyaluronic acid to treat recurrent UTI.

Ialuril

Freeman Hospital

Hyaluronate for the Treatment and Prevention of Recurrent Urinary Tract Infection in Women Suffering Atrophic Vaginitis

Occurrence of symptomatic UTI with prescription and taking of a treatment course of antibiotics for UTI. Applicable for both treatment arms in comparison to baseline established in the previous 12 months.

Occurrence of symptomatic UTI and the demonstration of a positive urine culture, rather than UTI symptoms potentially caused by interstitial cystitis without bacterial infection.

The two treatment arms will be compared to baseline to discover whether any improvement in vaginal atrophy symptoms are seen with either treatment. This will be assessed via questionnaires to determine symptoms experienced and their severity at 0 (baseline), 3, 6 and 9 months. Symptoms that participants will be asked to assess are as follows:
Frequency of urination
Urgency of urination
Pain or burning during urination
Partial bladder emptying
Fever or shivers
Pain in the lower abdomen or pelvis
Lower back pain
Blood in the urine Participants will rank the severity of these symptoms from "Did not have" to "Severe", and how troublesome they were from "Not at all" to "A lot" by marking a line to indicate where the participant feels their symptoms lie. Upon analysis of the questionnaires, placement of this mark will be measured and used to determine differences in symptoms from baseline throughout the study.

Urine samples will be analysed for the presence of bacteria. If any are found they will be cultured, identified and potentially undergo molecular typing to discover whether particular strains are more prevalent in patients suffering from concurrent rUTI and atrophic vaginitis.

Urine and vaginal douche samples will be collected at baseline and at 3-monthly intervals. These will be analysed by ELISA for the presence of innate immune markers and cytokines, such as defensins, interleukin-8 and lipocalin. A potential change in expression may indicate that this is partly how the treatments help to prevent against UTI.

Patient blood samples will be collected at baseline and DNA extracted. These will be examined for SNPs in genes such as TLR5, which encodes a receptor protein known to affect patient response to bacteria in cases of UTI.

Participants will be asked to complete questionnaires (EQ-5D) pertaining to their overall health and quality of life at baseline and at 3-monthly intervals to determine whether treatments are improving their overall health and general wellbeing at 0, 3, 6 and 9 months. This is a validated questionnaire commonly used in healthcare to determine general health and includes assessments of mobility, self-care, ability to carry out normal activity, pain/discomfort levels and anxiety/depression. This also asks participants to assess their overall health state by marking on a scale from 0-100, with higher numbers representing the best imaginable state of health.

Incidences of antibiotic use, in general and specifically for UTI, will be recorded to observe whether the treatments result in fewer courses of antibiotics being prescribed.

Newcastle-upon-Tyne Hospitals NHS Trust

The Urology Foundation, UK

Atrophic vaginitis and recurrent urinary tract infection are often found concurrently in post-menopausal women. The argument over which condition appeared first, or if one is caused by the other, is prevalent in clinical settings and there is no official guidance as to which should be treated first. We propose two arms to this study - one treating the atrophic vaginitis via use of Hyalofemme cream (hyaluronate cream), and the other treating recurrent UTI by use of Ialuril (hyaluronate bladder instillation). We intend to investigate the effect on the incidence of UTI in the patients with both treatments, as well as focusing on some markers of the immune response in the urine and vaginal douche samples from these participants.

Potato powder will be incorporated in the placebo product.

Several different berry powders including rose hip, bilberry, blackcurrant, sea buckthorn, and lingonberry will be prepared and studied.

Inflammation

Berry powder

University of Kristianstad

Berry Intake - Effects on Systemic and Oral Inflammation

Cecilia Widen

Researcher

Kristianstad University

Phase 1 (run-in): Marevan®
Phase 2: Marevan®
Phase 3: generic warfarin #1
Phase 4: generic warfarin #2

Phase 1 (run-in): generic warfarin #1
Phase 2: generic warfarin #1
Phase 3: Marevan®
Phase 4: generic warfarin #2

Phase 1 (run-in): generic warfarin #1
Phase 2: generic warfarin #1
Phase 3: generic warfarin #2
Phase 4: Marevan®

Phase 1 (run-in): Marevan®
Phase 2: Marevan®
Phase 3: generic warfarin #2
Phase 4: generic warfarin #1

Phase 1 (run-in): generic warfarin #2
Phase 2: generic warfarin #2
Phase 3: Marevan®
Phase 4: generic warfarin #1

Phase 1 (run-in): generic warfarin #2
Phase 2: generic warfarin #2
Phase 3: generic warfarin #1
Phase 4: Marevan®

Atrial Fibrillation

Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.

Marevan®

Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

generic warfarin #1

Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

generic warfarin #2

Hospital São Paulo/Hospital Universitário da UNIFESP (University Hospital of UNIFESP)

Therapeutic Equivalence Between Branded and Generic WARFArin Tablets in Brazil

Therapeutic Equivalence Between Branded and Generic Warfarin Sodium Tablets in Adult Patients With Atrial Fibrillation in Brazil - Crossover Randomized Controlled Equivalence Trial

INR: International normalized ratio. INR will be assessed twice a month during the 16 weeks of study.
Delta INR will be calculated by the difference, in absolute numbers (i.e. in module), between the two valid INR measurements due for each patient with each formulation at each period. Difference between the delta INRs will be the outcome. We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.

INR: International normalized ratio. INR will be assessed twice a month during the 16 weeks of study.
We will calculate the mean INR for each formulation of warfarin; difference between the mean INRs will be the outcome. We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.

The warfarin dosage will be calculated as the sum of the dosage taken in the week before the study visit, as referred by the patient. We will calculate the mean dosage for each formulation of warfarin; difference between the mean dosage will be the outcome.
We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.

Includes ischemic stroke (differential diagnosis with hemorrhagic stroke by tomography) and thromboembolism of viscera or extremities (diagnosed by acute symptoms and relevant diagnostic tests).

Classified as major or minor bleeding events.
Major: intracranial hemorrhage, fatal bleeding, bleeding resulting in hemoglobin loss equal to or greater than 2.0 g / L, hemorrhage requiring transfusion, bleeding in sensitive areas such as the retina or pericardium.
Minor: all other bleeding.

TTR calculated by Rosendaal Method also known as linear interpolation method. We will calculate the mean TTR for each formulation of warfarin; difference between the mean TTRs will be the outcome.
We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.

vaccinium bellum/hémorragie

Hyaluronate for the Treatment and Prevention of Recurrent Urinary Tract Infection in Women Suffering Atrophic Vaginitis

Berry Intake - Effects on Systemic and Oral Inflammation

Therapeutic Equivalence Between Branded and Generic WARFArin Tablets in Brazil

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