| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| complicated urinary tract infection (cUTI). |
|
| E.1.1.1 | Medical condition in easily understood language |
| A cUTI is an infection of the lower or upper urinary tract which can be caused by the presence of germs called bacteria. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 |
| To compare the composite outcome of clinical success and microbiologic success of intravenous (IV) HY-001 versus standard doses of colistin methanesulfonate (CMS; prodrug of colistin) monotherapy in patients with complicated urinary tract infection (cUTI) (with or without pyelonephritis) or acute uncomplicated pyelonephritis (AP) at risk for infection with multidrug resistant (MDR, according to Magiorakos 2012) Gram-negative pathogens in the microbiological Intent-to-Treat (microbiological-ITT) Population at Test-of-Cure (TOC) (approximately 7 days following the End-of-Treatment [EOT]). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
• To assess the safety and tolerability of IV HY-001
• To determine plasma and urine drug concentrations in a population of patients at various times.
• To assess microbiological and clinical response for each pathogen isolated at baseline and for each patient based on culture data obtained during treatment at Early Assessment (EA), EOT, and at Late Follow-up (LFU).
Exploratory:
Exposure-response relationship with regards to the antimicrobial activity of HY-001 and CMS alone
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Hospitalised patients with cUTI (with or without pyelonephritis) or AP at risk for infection with MDR Gram-negative pathogens, and who have provided written informed consent and willing and able to comply with all study procedures and activities
2. Patients who could receive CMS treatment as part of their standard care
3. Age ≥18 years and <80 years of age
4. BMI ≥18 to < 30 kg/m2
5. Patients who have a positive urine culture obtained within 48 hours before randomization containing ≥10^5 CFU/mL of a Gram-negative uropathogen are eligible for the study.
a. Patients may be enrolled before the results of the urine culture are available and treatment should NOT be delayed pending urine culture results
b. Patients with pathogens resistant or intermediate susceptible to colistin may continue to receive study drug upon the best clinical judgment of the Investigator
c. Patients who have a concomitant infection at the time of randomization that requires nonstudy systemic Gram-positive antibacterial therapy (medication with only Gram-positive activity [eg, vancomycin, daptomycin, linezolid] in addition to IV study drug, are allowed
6. Must have cUTI or acute complicated or uncomplicated pyelonephritis and must have ≥2 of the following acute signs and symptoms:
a. Chills or rigors or warmth associated with fever (eg. oral or tympanic temperature >38.0 C)
b. Flank pain (pyelonephritis) or pelvic pain
c. Nausea or vomiting
d. Dysuria, urinary frequency, or urinary urgency
e. Costo-vertebral angle tenderness (pyelonephritis) on physical examination
7. Provide a pretreatment adequate urine sample (the urine sample must return a positive culture for the patient to remain eligible for the study) obtained before administration of study drug or administration of any potentially effective antibiotic therapy against Gram-negative pathogens. A positive urine culture is defined as ≥10^5 CFU/mL of a causative uropathogen
a. If the patient’s pretreatment culture shows the presence of a colistin resistant or colistin intermediate susceptible pathogens after the patient has been enrolled, the Investigator must decide according to clinical signs and symptoms whether the patient can remain in the study
b. In the event of a negative urine culture, the patient must be prematurely discontinued from study drug and switched to standard-of-care treatment. A negative urine culture is one in which a pathogen with <10^5 CFU/mL is present
c. A urine culture is defined as contaminated if ≥1 causative pathogen with ≥10^5 CFU/mL is present AND ≥1 nonpathogen ≥10^5 CFU/mL are present
8. Have pyuria (ie, a dipstick analysis positive for leukocyte esterase or ≥10 white blood cells (WBCs) per cubic millimetre [1 μl]) in unspun urine, or ≥10 WBCs per high power field in spun urine
9. Be considered ill enough to be hospitalised for ≥5 days and require the initiation of parenteral therapy to manage cUTI by the standard of care
10. Contraception in women of childbearing potential must have been used for ≥2 months before starting the study; a documented negative highly sensitive serum pregnancy test must be provided and the patient must be nonlactating
11. If of non-childbearing potential, must be postmenopausal (ie, has had amenorrhea for ≥12 consecutive months) or surgically sterile for ≥6 months due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy
12. If of childbearing potential, agree to use a highly effective method of contraception, preferably with low user dependency; contraception is required during study treatment plus a 28-day period
a. Male patients must agree to use:
• Condom PLUS contraception for any non-pregnant partner who is a woman of childbearing potential during study treatment plus a 90-day period
b. Female patients must agree to use ≥1 of the following forms of contraception:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o oral
o intravaginal
o transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o injectable
o implantable
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomised partner, provided that partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomised partner has received medical assessment of the surgical success
• Sexual abstinence (only if the preferred and usual lifestyle) defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments; periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception |
|
| E.4 | Principal exclusion criteria |
| 1.Patient has a confirmed or suspected fungal or anaerobic UTI, or UTI caused by a Gram-positive pathogen or UTI caused by a pathogen kown or suspected to be intrinsically resistant to colistin;2.Patients with asymptomatic bacteriuria, the presence of >10^5 CFU/mL of a causative pathogen, and pyuria, but without local or systemic symptoms;3.Patient is receiving haemodialysis or peritoneal dialysis or has impairment of renal function including an estimated glomerular filtration rate <60 mL/min using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, requirement for peritoneal dialysis, or haemodialysis or hemofiltration;4.Concurrent use of onstudy systemic antibacterial and antimicrobial drug therapy with Gram-negative activity (including reverse transcriptase inhibitors) that would have a potential effect on outcome evaluations in patients with cUTI;5.Known hypersensitivity to CMS, colistin, other polymyxins, or zidovudine; 6.Uncomplicated cystitis in females;7.Having ileal loops, urinary diversion with bowel segments or suspected or confirmed vesicoureteral reflux, suspected or confirmed perinephric or intrarenal abscess; 8.History of renal transplant, any permanent complicating factors of the urinary tract that cannot be effectively treated during the therapy of the infection; 9.Indwelling urinary catheters expected to remain in place after therapy has been completed; 10.Any contraindication to the treatment with the individual medications according to the registered label; 11.Any infection that, in the opinion of the Investigator, would be considered intractable and likely to require >14 days of study drug;12.Any patient receiving a long-acting antibiotic with potentially effective Gram-negative activity or >1 dose of any antibiotic with potentially effective Gram-negative activity, within 72 hours before the first dose of study drug; 13.Previous participation in a clinical trial or treatment with investigational medication within the last 4 weeks or ≤5 half-lives, whichever is shorter, before starting study drug or patients who have not recovered from side effects of such investigational therapy; 14.Significantly immunocompromised (defined as a WBC <1000/μL) and/or having a known infection with human immunodeficiency virus (HIV);15.Any haematological malignancy, bone marrow transplantation, or current immunosuppressive therapy (including but not limited to cancer chemotherapy, or medications for prevention of organ transplantation rejection) or current treatment with reverse transcriptase inhibitors with Gram-negative activity; 16.Any concomitant psychiatric, neurological, or behavioural disorder including epilepsy or other lesions of the central nervous system sufficient in the opinion of the Investigator to prevent or compromise the patient’s participation in the study; 17.Any known concomitant bacterial or fungal sexually transmitted disease, except for candidiasis; 18.Having, in the opinion of the Investigator, any clinically significant serious or unstable physical illness likely to impact on the patient’s wellbeing or the conduct and analysis of the study, including, but not limited to, acute hepatic failure, respiratory failure, severe, persistent diarrhoea and septic shock; 19.Any malignant disease or a history of malignant neoplasm requiring a treatment with immune suppressive properties in the past 6 months before baseline; 20.Known history of drug or alcohol abuse; 21.Clinically significant abnormal haematology tests, chemistry tests, or urinalysis (UA, with the exception of the infection) results at baseline including, but not limited to:•AST,ALT,or alkaline phosphatase level >3 times the upper limit of normal (ULN)•Total bilirubin >2×ULN•WBC <1000/μL or >30,000/μL; platelet count <50,000/μL•Haematocrit <25%; 22.Any administration of therapeutic corticosteroids ≥20 mg of prednisone per day for >14 days before randomization; 23.Is an employee or relative of any involved study Investigator or any involved institution, including Sponsor or clinical research organization; 24.Is institutionalised because of a legal or regulatory order or have a legally acceptable representative; 25.Life expectancy <3 months; 26.Women who are pregnant or nursing;27.Is not eligible for treatment with colistin according to prescribing information of the standard of care CMS treatment;28.Any known or suspected hypersensitivity to, or known allergy to, or other intolerability to HY-001, CMS, ZVD, their active ingredient, or their excipients;29. Any other condition that, in the opinion of the Investigator, would prevent the patient from effectively participating in the study, place the patient at risk, or confound the ability to interpret data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is the combined outcome of clinical and microbiological response in the microbiological-ITT Population at TOC. To have an overall response, the patient must be both a clinical and microbiological success. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Primary endpoint is the combined outcome of clinical and microbiological response in the microbiological-ITT Population at TOC. To have an overall response, the patient must be both a clinical and microbiological success. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Early Assessment (EA; Day 4 or 5), End of Therapy (EOT, 7-14 days after start of therapy), Late Follow-up (LFU, 14 days after EOT) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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