Pan African Clinical Trials Registry

South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0835 or +27 21 938 0967
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202201760181404 Date of Registration: 21/01/2022
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title A COMPARATIVE BIOAVAILABILITY STUDY OF AN IMMEDIATE RELEASE TABLET FORMULATION CONTAINING 500 MG FLUCYTOSINE AND THREE SUSTAINED RELEASE PELLET FORMULATIONS OF FLUCYTOSINE IN HEALTHY SUBJECTS.
Official scientific title A COMPARATIVE, SINGLE CENTER, OPEN-LABEL, LABORATORY-BLIND, RANDOMIZED, FOUR PERIOD CROSSOVER STUDY TO DETERMINE THE RELATIVE BIOAVAILABILITY OF AN IMMEDIATE RELEASE TABLET FORMULATION CONTAINING 500 MG FLUCYTOSINE AND THREE SUSTAINED RELEASE PELLET FORMULATIONS OF FLUCYTOSINE IN HEALTHY MALES AND FEMALES UNDER FASTING CONDITIONS
Brief summary describing the background and objectives of the trial Background: Cryptococcal meningoencephalitis (CM) is a leading and preventable cause of AIDS-related mortality. Mortality for CM in resource limited settings is approximately 70% at 3 months, with many low- and middle-income countries (LMICs) having no access to diagnostics like the cryptococcal antigen lateral flow assay (CrAg LFAs) and essential medicines including flucytosine (5-FC). Over half to three quarters of people living with HIV (PLHIV) diagnosed with CM are now anti-retroviral therapy (ART) experienced, highlighting the urgent need for ongoing implementation of CM strategies in LMICs. CM in African LMICs has not gone away with ART roll out and is a pressing, preventable cause of advanced HIV disease (AHD) deaths. Significant research progress has occurred in past years leading to newly revised World Health Organization (WHO) CM treatment guidelines, however important challenges for deployment and scale-up remain. Short course amphotericin B (AmB) with 5-FC; 2 weeks’ 5 FC + fluconazole; and CrAg screening and pre-emptive therapy, are three mortality reducing strategies included in the new 2018 WHO CM guidelines [1] to become the new gold standard of care and treatment for LMICs. Recent studies show that these 5 FC regimens for confirmed CM cases can halve the mortality rates seen with the current use of fluconazole alone. Reducing the persistent mortality of PLHIV with AHD, affecting approximately one-third of patients presented to care in LMICs, is an urgent goal as per WHO’s 2017 guidelines on AHD management to achieve Sustainable Development Goals (SDGs). Objectives: To assess and compare the relative bioavailability of each of the three test products (Test 1, Test 2 and Test 3), flucytosine sustained-release (SR 5 FC) pellets (single dose: 1 x 3000 mg at 0 hours) and the reference product, immediate-release flucytosine (IR 5 FC) Ancotil® 500 mg tablets (3 x 500 mg at 0 hours and 3 x 500 mg at 6 hours after first dosing) under fasting condition
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Severe systemic fungal infections with susceptible pathogens
Purpose of the trial Treatment: Other
Anticipated trial start date 27/01/2022
Actual trial start date
Anticipated date of last follow up 07/03/2022
Actual Last follow-up date
Anticipated target sample size (number of participants) 36
Actual target sample size (number of participants)
Recruitment status Completed
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Crossover: all participants receive all interventions in different sequence during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Ancotil 500 IR Tablets 3000 mg (b.i.d. dose: 3 x 500 mg [0 hours] and 3 x 500 mg [6 hours]) Single Dose only per day. Immediate Release Tablets of 500 mg Ancotil 36 Active-Treatment of Control Group
Experimental Group Flucytosine SR Tablets 3000 mg Single Dose - 1 day Flucytosine 3000 mg sustained release pellets 36
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• Healthy males and females, 18 to 55 years (both inclusive) at the time of signing of informed consent. • Body mass index (BMI) between 18.5 and 30 kg/m2 (both inclusive). • Body weight not less than 50 kg for males and females. • Medical history, vital signs, physical examination, standard 12-lead ECG, including QT interval corrected with the Fridericia formula (QTcF) measure of ≤450 msec, and laboratory investigations must be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests, unless the investigator considers the deviation to be irrelevant for the purpose of the study. • Normal blood pressure (BP): Systolic BP between 90 and 140 (160 if > 45 years old) mmHg (inclusive), diastolic BP 45 to 90 mmHg (inclusive), measured after 10 min rest in supine position. • Non-smokers or mild to moderate smokers (≤ 10 cigarettes or pipes per day). • Females, if: • Not of childbearing potential, e.g., has been surgically sterilized, undergone a hysterectomy, amenorrhea for ≥ 12 months and considered post-menopausal (following follicle stimulating hormone [FSH] quantification). Note: In postmenopausal women, the value of the serum pregnancy test may be slightly increased. This test will be repeated once within a 1 week after the original test to confirm the results. If there is no increase indicative of pregnancy, the female will be included in the study. • Of childbearing potential, the following conditions are to be met: - Negative pregnancy test. If this test is positive, the subject will be excluded from the study. In the rare circumstance that a pregnancy is discovered after the subject received IP, every attempt must be made to follow her to term. - Not breastfeeding and must agree not to breastfeed while participating in the study and for up to 1 month after discontinuation of the treatment. - Abstaining from sexual activity (if this is the usual lifestyle of the subject) or are in a same-sex relationship or must agree to use • Evidence of psychiatric disorder, antagonistic functioning, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements. • Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol per week for females (1 unit is equal to approximately 330 mL of beer, one small glass [200 mL] of wine, or one measure [25 mL] of spirits). • Regular exposure to substances of abuse (other than alcohol) within the past year. • Use of any medication, prescribed or over-the-counter or herbal remedies, within 2 weeks before the first administration of IP except if this will not affect the outcome of the study in the opinion of the investigator. • Participation in another study with an experimental drug, where the last administration of the previous IP was within 8 weeks (or within 5 elimination half-lives for chemical entities or 2 elimination half-lives for antibodies or insulin, whichever is the longer) before administration of IP in this study. • Treatment within the previous 3 months before the first administration of IP with any drug with a well defined potential for adversely affecting a major organ or system. • Treatment with potent inhibitors of dihydropyrimidine dehydrogenase (DPD) in the previous 4 weeks: Antiviral antiherpetic nucleoside agents (e.g. brivudine, sorivudine and their analogues) or Uracil. • Known dihydropyrimidine dehydrogenase (DPD) deficiency. • Treatment with a not recommended and contraindicated medication as per SmPC within 2 weeks before the first administration of IP. • A major illness during the 3 months before commencement of the screening period. • History of hypersensitivity or allergy to the IP or its excipients or any related medication. • History of bronchial asthma or any other bronchospastic disease. • History of convulsions. • History of porphyria. • Relevant history or laboratory or clinical findings Adolescent: 13 Year(s)-17 Year(s),Adult: 18 Year(s)-44 Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 55 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 23/03/2021 Health Sciences Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Block D, Room 108, Francois Retief Building, University of the Free State, Nelson Mandela Drive Bloemfontein 9300 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 03/03/2021 SAHPRA
Ethics Committee Address
Street address City Postal code Country
Building A Loftus Park Kirkness Street Arcadia Pretoria 0001 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 01/04/2021 Department Health Republic of South Africa
Ethics Committee Address
Street address City Postal code Country
Civitas Building, c/o Struben and Thabo Sehume Streets Pretoria 0001 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome To assess and compare the relative bioavailability of each of the three test products (Test 1, Test 2 and Test 3), flucytosine sustained-release (SR 5 FC) pellets (single dose: 1 x 3000 mg at 0 hours) and the reference product, immediate-release flucytosine (IR 5 FC) Ancotil® 500 mg tablets (3 x 500 mg at 0 hours and 3 x 500 mg at 6 hours after first dosing) under fasting conditions. Pharmacokinetics
Secondary Outcome To evaluate the safety and tolerability of the test and reference products in healthy males and females under fasting conditions. Safety
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
FARMOVS Clinical Research Unit Nelson Mandela drive Bloemfontein 9300 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Drugs for Neglected Diseases Initiative 15 Chemin Louis-Dunant Geneva 1202 Switzerland
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Drugs for Neglected Diseases initiative 15 Chemin Louis-Dunant Geneva 1202 Switzerland NGO
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Edrich Krantz Edrich.Krantz@farmovs.com 0027514103091 Nelson Mandela Drive
City Postal code Country Position/Affiliation
Bloemfontein 9301 South Africa Senior Clinical Research Physician
Role Name Email Phone Street address
Public Enquiries Johan Fourie johan.fourie@farmovs.com 0027514109512 Nelson Mandela Drive
City Postal code Country Position/Affiliation
Bloemfontein 9301 South Africa Project Manager
Role Name Email Phone Street address
Scientific Enquiries Yolandi Swart Yolandi.Swart@farmovs.com 0027514103279 Nelson Mandela Drive
City Postal code Country Position/Affiliation
Bloemfontein 9301 South Africa Medical Director
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data that underlines the results reported in this trail, after de-identification, will be written up in a Clinical Study Report (CSR). Copies of the CSR will be provided to the Research Ethics Committee (REC) and the South African Health Products Authority (SAHPRA) in accordance with regulatory requirements and FARMOVS SOPs. Publication of Results: If a publication (e.g., in a scientific journal) based on the results of this study is envisaged by FARMOVS, approval from the sponsor will be obtained and a draft manuscript will be submitted to the sponsor for scrutiny and comment. The choice of conduit will be mutually agreed on by the principal investigator and the sponsor. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol Immediately after the Clinical Study Report has been finalized i.e. expected around Dec 2022 ImmediFARMOVS collects, processes and transfers trial participants’ and volunteers’ personal data (as defined in a policy) in accordance with sponsors’ and the Client instructions and applicable laws (POPI Act), regulations and guidelines and complies with safeguards and data limitations required by relevant health authorities or ethics committees. FARMOVS processes personal data on behalf of the clients and / or trial sites and recognises and protects the data protection and privacy-related rights of trial participants and volunteers in the context of clinical research and compassionate use programs. As a condition of participating in a clinical study, or the intention of doing so; and in advance of collecting personal data, trial participants must sign informed consent forms (ICFs) that comply with applicable clinical research and data protection laws. The confidentiality of records that could identify trial participants should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). The Company collects and processes only those elements of personal data that are required to meet its obligations under agreements with clients. FARMOVS has appropriate technical and organisational security measures to prevent unauthorised or unlawful disclosure of personal data.ately after the Clinical Study Report has been finalized i.e. expected around Dec 2022
URL Results Available Results Summary Result Posting Date First Journal Publication Date
Yes 22/06/2023
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result - 22/06/2023
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information