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Trial registered on ANZCTR


Registration number
ACTRN12620000037909
Ethics application status
Approved
Date submitted
22/11/2019
Date registered
21/01/2020
Date last updated
17/09/2020
Date data sharing statement initially provided
21/01/2020
Date results information initially provided
17/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Open-Label, Four-Period, Two-Sequence, Two-Treatment, Single Dose, Randomized, Crossover Bioequivalence Study of a Test Tablet Formulation of Ravidasvir with the Reference Tablet Formulation of Ravidasvir in Healthy Adult Volunteers Under Fasting Conditions
Scientific title
A Phase 1, Open-Label, Four-Period, Two-Sequence, Two-Treatment, Single Dose, Randomized, Crossover Bioequivalence Study of a Test Tablet Formulation of Ravidasvir with the Reference Tablet Formulation of Ravidasvir in Healthy Adult Volunteers Under Fasting Conditions
Secondary ID [1] 299889 0
NMRR-19-3221-51840
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis C Virus (HCV) 315311 0
Condition category
Condition code
Infection 313611 313611 0 0
Other infectious diseases
Oral and Gastrointestinal 314192 314192 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In the First group, the Comparator Treatment Ravidasvir Reference product will be administered as a single dose of 200 mg [1 x 200 mg] tablet on Day 1 and Day 15 with approximately 240 mL of ambient temperature water under fasted conditions. On day 8 and Day 22, the First group will receive a single dose of 200 mg [1 x 200 mg] tablet of the Interventional Treatment Ravidasvir Test product with approximately 240mL of ambient temperature water under fasted conditions. Each dose of RDV (first dose on Day 1, second dose on Day 8, third dose on Day 15 and last done on Day 22) will be separated by a washout period of at least 7 days.
In the Second group, the Interventional Treatment Ravidasvir Test product will be administered as a single dose of 200 mg [1 x 200 mg] tablet on Day 1 and Day 15 with approximately 240 mL of ambient temperature water under fasted conditions. On day 8 and Day 22, the Second group will receive a single dose of 200 mg [1 x 200 mg] tablet of the Comparator Treatment Ravidasvir Reference product with approximately 240mL of ambient temperature water under fasted conditions. Each dose of RDV (first dose on Day 1, second dose on Day 8, third dose on Day 15 and last done on Day 22) will be separated by a washout period of at least 7 days.
To ensure that subjects will be under fasted conditions, they will be admitted the day before the dosing day at the admission unit. They will be fasting since 10:00 pm until until 4 hours after dosing (total 14 hours). Water only will be allowed except during 1 hour before and 1 hour after dosing.
Patients will stay at the admission unit during 3 days
Intervention code [1] 316159 0
Treatment: Drugs
Comparator / control treatment
The comparator is the same active product ingredient produced by another company (CAD Middle East Pharmaceutical Industries LLC, Saudi Arabia)
Control group
Active

Outcomes
Primary outcome [1] 322060 0
To compare the rate and extent of absorption for Ravidasvir when administered as a single 200 mg oral dose of the proposed commercial product (“test”) produced by Doppel Farmaceutici using the Pharco B international API with the clinical trial product (“reference”) manufactured by Doppel Farmaceutici using CAD Middle East Pharmaceutical Industries LLC API in healthy volunteers, under fasted conditions.
Timepoint [1] 322060 0
Plasma Ravidasvir Cmax, area under the plasma concentration-time curve from time of intake until infinity (AUC0-8), and area under the plasma concentration-time curve from time of intake until the last quantifiable concentration (AUC0-t) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Secondary outcome [1] 377175 0
To assess the safety and tolerability of single oral doses of both Ravidasvir formulations in healthy volunteers bymonitoring clinical adverse events (AEs), vital signs, 12-lead ECGs, safety-related clinical laboratory tests (clinical chemistry, haematology, and urinalysis), and physical examinations.
Timepoint [1] 377175 0
These assessments will be performed on Day prior to Dosing day for each period: Day 0, Day 7 , Day 14 and Day 21. Vital signs assessments will be performed on dosing day of each period: Day 1, Day 8, Day 15 and Day 22. Physical examintations and vital signs assessments will be performed on last day of each period: Day 3, Day 10, Day 17 and Day 24. A post-study safety assemment visit will be performed after last period on Day 29.
Secondary outcome [2] 377861 0
Secondary plasma PK outcomes include time to reach the maximum plasma concentration (tmax), mean residence time (MRT), elimination rate constant (delta z), elimination half-life (t1/2, estimated based on deltaz), apparent volume of distribution, terminal phase (Vz/F), and apparent clearance (CL/F).
Timepoint [2] 377861 0
pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose for each of the four periods.

Eligibility
Key inclusion criteria
Healthy volunteers must meet all of the following inclusion criteria to be eligible for participation in this study:

• Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
• Must be between 18 and 55 years of age, inclusive, at the date of ICF signature
• Must be a non-smoker or an ex-smoker for more than 90 days. The use of nicotine or nicotine-containing products or electronic cigarettes must be discontinued 90 days prior to the first admission day of the study.
• Must have a calculated body mass index (BMI) of 18.0 to 29.9 kg/m2.
• Must be HIV-1 antibody negative.
• Must be hepatitis B (HBV) surface antigen negative.
• Must be hepatitis C (HCV) antibody negative.
• Females must have a negative serum pregnancy test at Screening and on Day 0.
• Females of childbearing potential must agree to utilize highly effective contraception methods (with the exception of hormonal contraceptive) from 3 weeks prior to baseline (Day 0) throughout the duration of study treatment and for 30 days following the last dose of study drug.
• Men who participate in this study must not father a child and must agree to use contraceptive protection in the form of a double barrier method (condom or diaphragm) from the moment they sign the ICF until the Post-Study Safety Assessment.
• Healthy volunteers must, in the opinion of the Investigator, be in good health based upon medical history, physical examination (including vital signs), and screening laboratory evaluations (haematology, chemistry, and urinalysis) must fall within the normal range of the local laboratory's reference ranges unless the results have been determined and documented by the Investigator to have no clinical significance.
• Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered not clinically significant by the Investigator. QTcF measure should be less than or equal to 450 msec (male) or than or equal to 470 msec (female).
• Must have negative urine screen for drugs of abuse (including but not limited to ketamine, amphetamines, tetrahydrocannabinol, morphine, methamphetamine, and benzodiazepines)
• Must be willing and able to comply with all study requirements.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers who meet any of the following exclusion criteria are not to be enrolled in this study:
• Healthy volunteers with any hematologic or urinary analyte that is outside the normal limits of the study laboratory and have been determined by the Investigator to have clinical significance at Screening will be excluded
• Pregnant or lactating female healthy volunteers.
• Female healthy volunteers who utilize hormonal contraceptive as one of their birth control methods.
• Have any serious past or active medical condition or psychiatric illness which, in the opinion of the Investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include renal, cardiac, hematologic, hepatic, pulmonary (including chronic asthma), endocrine (e.g., diabetes), central or peripheral nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), surgery (e.g stomach bypass) or immunodeficiency disorders, active infection, or malignancy that is clinically significant or requiring treatment.
• Have participated in an investigational trial involving administration of any investigational compound within 90 days prior to the study dosing or 5-times the half-life of the drug tested in the previous clinical trial, whichever is longer (time calculated relative to the last dose in the previous clinical trial).
• Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance.
Regular alcohol consumption in males greater than 21 units per week and females greater than 14 units per week (1 unit equal ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units equal 125 mL glass of wine, depending on type). As confirmed by a positive alcohol breath test either at screening or at admission day.
• Have donated or lost blood (greater than or equal to 450ml) within three months of study dosing.
• Have donated plasma within 7 days of study dosing.
• Have difficulty in swallowing solids like tablets.
• Have taken any prescription medications or over-the-counter medications including herbal products within 1 week of commencing study drug dosing with the exception of vitamins (without herbal compounds) and/or paracetamol and/or ibuprofen.
• Have a history of significant drug allergy.
• Smokers as confirmed by a breath carbon monoxide (Smokerlyzer) reading of greater than 10 ppm at screening or at admission day, and users of electronic cigarette.
• Unable and/or unwilling to comply with study requirements.
• Believed by the study Investigator to be inappropriate for study participation for any reason

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Bio-equivalence
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 22139 0
Malaysia
State/province [1] 22139 0
Kuala Lampur

Funding & Sponsors
Funding source category [1] 304346 0
Other Collaborative groups
Name [1] 304346 0
Drug for Neglected Diseases initiative
Address [1] 304346 0
15 chemin Louis-Dunant
1202 Genève
Country [1] 304346 0
Switzerland
Primary sponsor type
Other Collaborative groups
Name
Drug for Neglected Diseases initiative
Address
15 chemin Louis-Dunant
1202 Genève
Country
Switzerland
Secondary sponsor category [1] 304599 0
None
Name [1] 304599 0
Address [1] 304599 0
Country [1] 304599 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304798 0
Malaysian Research Ethic Committee (MREC)
Ethics committee address [1] 304798 0
Secretary Secretariat of National Institutes of Health (NIHSEC) c/o No. 1 Jalan Setia Murni U13/52
Seksyen U13 Bandar Setia Alam
40170 Shah Alam.
Ethics committee country [1] 304798 0
Malaysia
Date submitted for ethics approval [1] 304798 0
18/11/2019
Approval date [1] 304798 0
17/01/2020
Ethics approval number [1] 304798 0
NMRR-19-3221-51840 (ISR)
Ethics committee name [2] 305271 0
National Pharmaceutical Regulatory Agency (NPRA)
Ethics committee address [2] 305271 0
Centre fo Investigational New Product
National Pharmaceutical Control Bureau
Lot 36, Jalan University
46200 Petaling Jaya
Selangor
Malaysia
Ethics committee country [2] 305271 0
Malaysia
Date submitted for ethics approval [2] 305271 0
20/11/2019
Approval date [2] 305271 0
21/01/2020
Ethics approval number [2] 305271 0
PBKD/LK-20190214

Summary
Brief summary
Ravidasvir, is being developed for the treatment of Hepatitis C, a liver disease caused by a virus (HCV). Ravidasvir is a NS5A inhibitor, which exhibits potent inhibition of HCV replication in HCV replicon assays. In an ongoing phase II/III study, it was hypothesized that sofosbuvir plus ravidasvir constitutes a pan-genotypic, potent and safe regimen which can be used in decentralized public health settings under the supervision of appropriately trained health care professionals. Such a combination will not require intensive pre-treatment evaluation or monitoring and can thus be scaled up together with active identification and linkage to care of HCV infected persons. 301 patients were included in the study and preliminary data are very promising. During the course of development, a new batch of ravidasvir tablets has been prepared by the proposed commercial manufacturer (Doppel Farmaceutici, Italy) with an Active Pharmaceutical Ingredient (API) manufactured by Pharco B International (Egypt). Tablets manufactured from the Pharco B international API are intended to be used in subsequent clinical trials and be registered as the commercial product.
We are doing this assay to assess if ravidasvir 200 mg tablets supplied by Doppel Farmaceutici from CAD Middle East Pharmaceutical Industries LLC (Saudi Arabia) API and tablets from Doppel Farmaceutici from the Pharco B international API are bioequivalent.
The study will be done at a single site: Clinical Research Ward at Ampang Hospital.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98242 0
Dr Sharon Ng Shi Min
Address 98242 0
Clinical Research Ward (CRW)
Clinical Trial Unit, Level 7, Hospital Ampang
68000 Ampang, Selangor
Country 98242 0
Malaysia
Phone 98242 0
+603 4289 6558
Fax 98242 0
Email 98242 0
sharonng@crc.gov.my
Contact person for public queries
Name 98243 0
Dr Sharon Ng Shi Min
Address 98243 0
Clinical Research Ward (CRW)
Clinical Trial Unit, Level 7, Hospital Ampang
68000 Ampang, Selangor
Country 98243 0
Malaysia
Phone 98243 0
+603 4289 6558
Fax 98243 0
Email 98243 0
sharonng@crc.gov.my
Contact person for scientific queries
Name 98244 0
Dr Nabila Ibnou Zekri Lassout
Address 98244 0
DNDi
15 chemin Louis-Dunant
1202 Genève
Country 98244 0
Switzerland
Phone 98244 0
+41225551956
Fax 98244 0
Email 98244 0
nzekri@dndi.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary