Randomized, Open-label Phase 2 Study of Oral AZD0914 in the Treatment of Gonorrhea

Study Overview
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Brief Summary
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This is a multi-center Phase 2 randomized, open-label study in approximately 180 adult male and female subjects, between the ages of 18 and 55, who are in good health and meet all eligibility criteria. The study is designed to assess the safety and efficacy of an antimicrobial investigational product, AZD0914 manufactured by AstraZeneca, administered to adults to treat uncomplicated urogenital gonorrhea compared to treatment with ceftriaxone. Subjects will be randomly assigned 70:70:40 to receive a single, oral dose of 2000 mg of AZD0914, 3000 mg of AZD0914, or intramuscular dose of 500 mg of ceftriaxone. The drug name is also known as ETX0914.

Detailed Description
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Uncomplicated gonorrhea is currently the second most common bacterial sexually transmitted infection (STI) worldwide and, accordingly, is a serious public health problem. This is a multi-center Phase 2 randomized, open-label study in approximately 180 adult male and female subjects, between the ages of 18 and 55, with uncomplicated cervical or urethral gonorrhea. The study is designed to assess the safety and efficacy of an antimicrobial investigational product, AZD0914 manufactured by AstraZeneca, administered to adults to treat uncomplicated urogenital gonorrhea compared to treatment with intramuscular ceftriaxone. Subjects will be randomly assigned 70:70:40 to receive a single, oral dose of 2000 mg of AZD0914, 3000 mg of AZD0914, or intramuscular dose of 500 mg of ceftriaxone. The study duration is 11 months and subject participation of 30 days. Subjects with 1) untreated urethral or cervical gonorrhea identified via laboratory testing at a prior visit, or 2) untreated subjects acknowledging anal, oral, or vaginal sexual contact in the past 14 days with someone diagnosed with gonorrhea, or 3) signs and symptoms of urethral or cervical gonorrhea will be offered enrollment in the study and consented. The primary objective assess the efficacy by microbiological cure rate of 2000 mg or 3000 mg AZD0914 compared to 500 mg ceftriaxone for the treatment of uncomplicated urogenital gonorrhea. The second primary objective assess the safety and tolerability of a single oral dose of 200 mg or 3000 mg AZD0914 compared to 500 mg ceftriaxone in adult subjects with uncomplicated urogenital gonorrhea. The drug name is also known as ETX0914.

Official Title
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A Randomized, Open-label Phase 2 Study to Evaluate the Efficacy and Safety of a Single Dose of Oral AZD0914 Compared to Intramuscular Ceftriaxone in the Treatment of Male and Female Subjects With Uncomplicated Gonorrhea

Conditions
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Gonorrhoea

Intervention / Treatment
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* Drug: AZD0914
* Drug: Ceftriaxone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Untreated subjects with signs and symptoms of urethral or cervical gonorrhea, or confirmed urethral or cervical gonorrhea* or any type of sexual contact in the past 14 days with an infected individual. *As defined by positive culture, NAAT test, or Gram-stain 2. Subject is able to give voluntary written informed consent before any study related procedure is performed 3. Willingness to comply with all protocol requirements 4. Male or non-pregnant female 18 to 55 years of age, inclusive 5. If the subject is female, a negative urine pregnancy test at Visit 1 prior to receiving study drug 6. Subject willing to abstain from anal, oral, and vaginal sexual intercourse or use condoms for 7 days following study drug dosing to prevent potential gonococcal reinfection 7. Male subjects must be surgically sterilized or use condoms for 7 days following study drug dosing 8. Female subject must be of non-childbearing potential* or if of childbearing potential, she must be using a highly effective method of birth control** *Non-childbearing potential is defined as being post-menopausal for at least two years, status after bilateral oophorectomy or status after hysterectomy. **Female subjects must avoid becoming pregnant by using one of the following acceptable methods of birth control for 30 days prior to study drug dosing: --Intrauterine contraceptive device; OR --Oral contraceptives; OR --Implanon®,Nexplanon®, DepoProvera®, contraceptive skin patch or NuvaRing®, OR --Tubal ligation OR --Abstinence AND --for 30 days following dosing, any method above should be used plus the required use of a barrier method (condom) by the male partner (even if vasectomized) Exclusion Criteria: 1. Confirmed or suspected, complicated or systemic gonorrhea such as pelvic inflammatory disease, testicular pain, epididymitis, arthritis, conjunctivitis or endocarditis or clinical proctitis. 2. Known concomitant infection which would require immediate additional systemic antibiotics 3. Female subject currently breastfeeding 4. Use of any systemic or intravaginal antibiotics with activity against N. gonorrhoeae or systemic antivirals within 30 days prior to study drug administration (topical and intravaginal antifugals are permitted). 5. Use of systemic corticosteroid drugs or other immunosuppressive therapy within 30 days prior to enrollment 6. Cytotoxic chemotherapy or radiation therapy within the previous 3 months 7. Known chronic renal, hepatic (including chronic hepatitis B or hepatitis C infection) or hematologic impairment, or other condition that could interfere with the absorption or metabolism of study drug 8. Any concomitant condition that, in the opinion of the Investigator, would preclude an evaluation of a response or make it unlikely that the course of therapy and follow-up could be completed 9. Subject HIV-infected and taking antiretroviral medication -- Subject not HIV-infected and taking antiretroviral for pre- or post- exposure prophylaxis -- Subject newly diagnosed with HIV infection or known to be HIV infected with evidence of immunosuppression, such as documented or patient reported CD4 count of < 200 10. Known allergy to cephalosporin or penicillin antibiotics 11. Receipt or planned receipt of an investigational product in a clinical trial within 30 days prior to or 7 days after study dose administration 12. Female subject is not willing to defer treatment for bacterial vaginosis until Visit 2 if she tests positive for bacterial vaginosis at Visit 1. 13. Use of drugs that act as inducer/inhibitors of CYP3A4/5 or the P-gp efflux transporter* within 30 days prior to study drug administration *such as itraconozale, fluconazole, ketoconazole, verapamil, diltiazem, amiodarone, felodipine, carbamazepine, phenytoin, or St. John's wort 14. Subjects known to be co-infected with chlamydia prior to study entry 15. Subjects with medically documented cardiac arrhythmia 16. Known allergy to lidocaine (or local anesthetics of the amide type, e.g., articaine, bupivacaine, mepivacaine, prilocaine, ropivacaine) or the antimicrobial preservative methylparaben.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>N = 70 subjects receive single oral dose , 2000 mg of AZD0914 | Drug: AZD0914<br>* AZD0914 is an antimicrobial amorphous nonsterile powder. Group 1 receive 2000 mg; Group 2 receive 3000 mg. The drug name is also known as ETX0914.<br>|
| Experimental: Group 2<br>N =70 subjects receive single oral dose , 3000 mg of AZD0914 | Drug: AZD0914<br>* AZD0914 is an antimicrobial amorphous nonsterile powder. Group 1 receive 2000 mg; Group 2 receive 3000 mg. The drug name is also known as ETX0914.<br>|
| Active Comparator: Group 3<br>N = 40 subjects receive single intramuscular dose, 500 mg of ceftriaxone | Drug: Ceftriaxone<br>* Ceftriaxone is a broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to meninges, eyes and inner ears. A white to yellowish orange crystalline powder. Group 3 receives 500 mg reconstituted with 1 ml Lidocaine HCL 1%, intramuscularly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Microbiological Cure at Urethral or Cervical Sites in Each Study Arm | Microbiological cure was assessed at the Test of Cure visit (TOC). Microbiological Cure was derived from the Neisseria gonorrhoeae culture result and assessed by anatomical site. Male participants were swabbed at the urethral site and female participants at the cervical site. Remel RapID NH tests were performed on pure cultures obtained from swab specimens. A participant was defined as a microbiological cure if N. gonorrhoeae was not detectable by culture at TOC. | Day 6 | 
| Number of Participants Reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) Considered Product-related. | Adverse events are defined as any untoward medical occurrence regardless of its causal relationship to the study treatment. Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation thereof was a congenital anomaly/birth defect; or may have jeopardized the subject or required intervention to prevent one of the outcomes. Relationship to study product was determined by the investigator and defined as a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event. | Day 1 through Day 31 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Microbiological Cure at Rectal Sites in Each Study Arm | Microbiological cure was assessed at the TOC visit. Microbiological cure was derived from the Neisseria gonorrhoeae culture result and assessed by anatomical site. All participants were swabbed at the rectal site. Remel RapID NH tests were performed on pure cultures obtained from swab specimens. A subject was defined as a microbiological cure if N. gonorrhoeae was not detectable by culture at TOC. | Day 6 | 
| Number of Participants With Microbiological Cure at Pharyngeal Sites in Each Study Arm | Microbiological cure was assessed at the Test of Cure visit (TOC). Microbiological Cure was derived from the Neisseria gonorrhoeae culture result and assessed by anatomical site. All subjects were swabbed at the pharyngeal site. Remel RapID NH tests were performed on pure cultures obtained from swab specimens. A participant was defined as a microbiological cure if N. gonorrhoeae was not detectable by culture at TOC. | Day 6 | 
| Number of Participants With Clinical Cure in Each Study Arm | A clinical cure was defined as the resolution of all signs and symptoms of gonorrhea (e.g. cervical/vaginal/urethral discharge, dysuria, dyspareunia, vulvovaginal irritation, sore throat) that were present at enrollment with the exception of vaginal discharge due to yeast vaginitis or bacterial vaginosis. A clinical failure was defined by the presence of any sign or symptom of gonorrhea that was also present at enrollment with the exception of vaginal discharge due to yeast vaginitis or bacterial vaginosis. The investigator also submitted his/her determination of whether the participant met or did not meet the criteria for clinical cure (or whether it is unknown if the participant met the criteria). In the event the investigator's assessment of clinical cure did not coincide with the definitions of clinical cure/failure, the investigator's assessment was the final adjudicator. | Day 6 | 
| Number of Participants With no Detectable N. Gonorrhoeae Nucleic Acid in Urethral/Cervical Specimens in Each Study Arm at Baseline. | Gonorrhea and Chlamydia nucleic acid amplification tests (GC/CT NAAT) were performed at baseline with specimens collected at the cervical/urethral site. Detectable nucleic acid was derived from GC/CT NAAT testing. If N. gonorrhoeae nucleic acid was detected, the result of the test was classified as positive. If no nucleic acid was detected, the result of the test was classified as negative. If a clear result could not be determined for any reason, the result of the test was classified as indeterminate. | Day 1 (Baseline) | 
| Number of Participants With no Detectable N. Gonorrhoeae Nucleic Acid in Urethral/Cervical Specimens in Each Study Arm at Day 6. | Gonorrhea and Chlamydia nucleic acid amplification tests (GC/CT NAAT) were performed at Day 6 with specimens collected at the cervical/urethral site. Detectable nucleic acid was derived from GC/CT NAAT testing. If N. gonorrhoeae nucleic acid was detected, the result of the test was classified as positive. If no nucleic acid was detected, the result of the test was classified as negative. If a clear result could not be determined for any reason, the result of the test was classified as indeterminate. | Day 6 | 
| Number of Participants With no Detectable N. Gonorrhoeae Nucleic Acid in Rectal Specimens in Each Study Arm | Gonorrhea and Chlamydia nucleic acid amplification tests (GC/CT NAAT) were performed at baseline and Day 6 with specimens collected at the rectal site. Detectable nucleic acid was derived from GC/CT NAAT testing. If N. gonorrhoeae nucleic acid was detected, the result of the test was classified as positive. If no nucleic acid was detected, the result of the test was classified as negative. If a clear result could not be determined for any reason, the result of the test was classified as indeterminate. | Baseline and Day 6 | 
| Number of Participants With no Detectable N. Gonorrhoeae Nucleic Acid in Pharyngeal Specimens in Each Study Arm | Gonorrhea and Chlamydia nucleic acid amplification tests (GC/CT NAAT) were performed at baseline and Day 6 with specimens collected at the pharyngeal site. Detectable nucleic acid was derived from GC/CT NAAT testing. If N. gonorrhoeae nucleic acid was detected, the result of the test was classified as positive. If no nucleic acid was detected, the result of the test was classified as negative. If a clear result could not be determined for any reason, the result of the test was classified as indeterminate. | Baseline and Day 6 | 
| Median in Vitro Minimum Inhibitory Concentrations (MIC) Against AZD0914/ETX0914 and Ceftriaxone of Gonococcal Isolates From Culture of Isolates From the Urethral/Cervical Sites at Baseline | For all positive cultures of specimens collected from the urethra or cervix, isolates were collected and tested for antimicrobial susceptibility profiles and the minimum inhibitory concentration (MIC) was determined. MIC was defined as the lowest concentration of an antimicrobial that inhibited the visible growth of a microorganism after overnight incubation. The MIC breakpoint was a chosen concentration of an antibiotic which defines whether a bacterial isolate is susceptible or resistant to the antibiotic. If the MIC was less than or equal to the susceptibility breakpoint, the bacteria was considered susceptible to the antibiotic. If the MIC was greater than this value, the bacteria was considered intermediate or resistant to the antibiotic. | Day 1 (Baseline) | 
| Median in Vitro MIC Against AZD0914/ETX0914 and Ceftriaxone of Gonococcal Isolates From Culture of Isolates From the Urethral/Cervical Sites at Day 6 | For all positive cultures of specimens collected from the urethra or cervix, isolates were collected and tested for antimicrobial susceptibility profiles and the MIC was determined. MIC was defined as the lowest concentration of an antimicrobial that inhibited the visible growth of a microorganism after overnight incubation. The MIC breakpoint was a chosen concentration of an antibiotic which defines whether a bacterial isolate is susceptible or resistant to the antibiotic. If the MIC was less than or equal to the susceptibility breakpoint, the bacteria was considered susceptible to the antibiotic. If the MIC was greater than this value, the bacteria was considered intermediate or resistant to the antibiotic. | Day 6 | 
| Median in Vitro MIC Against AZD0914/ETX0914 and Ceftriaxone of Gonococcal Isolates From Culture of Isolates From the Rectal Site at Baseline | For all positive cultures of specimens collected from the rectum, isolates were collected and tested for antimicrobial susceptibility profiles and the MIC was determined. MIC was defined as the lowest concentration of an antimicrobial that inhibited the visible growth of a microorganism after overnight incubation. The MIC breakpoint was a chosen concentration of an antibiotic which defines whether a bacterial isolate is susceptible or resistant to the antibiotic. If the MIC was less than or equal to the susceptibility breakpoint, the bacteria was considered susceptible to the antibiotic. If the MIC was greater than this value, the bacteria was considered intermediate or resistant to the antibiotic. | Day 1 (Baseline) | 
| Median in Vitro MIC Against AZD0914/ETX0914 and Ceftriaxone of Gonococcal Isolates From Culture of Isolates From the Rectal Site at Day 6 | For all positive cultures of specimens collected from the rectum, isolates were collected and tested for antimicrobial susceptibility profiles and the MIC was determined. MIC was defined as the lowest concentration of an antimicrobial that inhibited the visible growth of a microorganism after overnight incubation. The MIC breakpoint was a chosen concentration of an antibiotic which defines whether a bacterial isolate is susceptible or resistant to the antibiotic. If the MIC was less than or equal to the susceptibility breakpoint, the bacteria was considered susceptible to the antibiotic. If the MIC was greater than this value, the bacteria was considered intermediate or resistant to the antibiotic. | Day 6 | 
| Median in Vitro MIC Against AZD0914/ETX0914 and Ceftriaxone of Gonococcal Isolates From Culture of Isolates From the Pharyngeal Site at Baseline | For all positive cultures of specimens collected from the pharynx, isolates were collected and tested for antimicrobial susceptibility profiles and the MIC was determined. MIC was defined as the lowest concentration of an antimicrobial that inhibited the visible growth of a microorganism after overnight incubation. The MIC breakpoint was a chosen concentration of an antibiotic which defines whether a bacterial isolate is susceptible or resistant to the antibiotic. If the MIC was less than or equal to the susceptibility breakpoint, the bacteria was considered susceptible to the antibiotic. If the MIC was greater than this value, the bacteria was considered intermediate or resistant to the antibiotic. | Day 1 (Baseline) | 
| Median in Vitro MIC Against AZD0914/ETX0914 and Ceftriaxone of Gonococcal Isolates From Culture of Isolates From the Pharyngeal Site at Day 6 | For all positive cultures of specimens collected from the pharynx, isolates were collected and tested for antimicrobial susceptibility profiles and the MIC was determined. MIC was defined as the lowest concentration of an antimicrobial that inhibited the visible growth of a microorganism after overnight incubation. The MIC breakpoint was a chosen concentration of an antibiotic which defines whether a bacterial isolate is susceptible or resistant to the antibiotic. If the MIC was less than or equal to the susceptibility breakpoint, the bacteria was considered susceptible to the antibiotic. If the MIC was greater than this value, the bacteria was considered intermediate or resistant to the antibiotic. | Day 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibiotic, antimicrobial, AZD0914, Ceftriaxone, drug-resistant, sexually transmitted infection, urogenital gonorrhoea