Prequalification
Roadmap
DPP Prequalification
All formulation development and manufacture of the pilot and clinical batches will be conducted according to current Good Manufacturing Practice (cGMP), while the analyses will be performed in a GLP certified laboratory, following WHO international quality standards.
BE study
This classic, randomised, two-way, cross-over bioequivalence study will follow WHO guidelines. It will be conducted in Addis Ababa, Ethiopia, in male and female adult heathy normal volunteers (HNVs) who are not G6PD deficient, allergic to primaquine or have any exclusion criteria found in their laboratory tests and medical history.
Based on previous pharmacokinetic evaluations of primaquine and carboxyprimaquine in human normal volunteers, up to 50 volunteers will be enrolled. They will be admitted to the hospital and randomised to receive either one 15 mg tablet of reference or test PQ on an empty stomach with a standard volume of water (e.g. 150 mL). Blood samples will be taken intensely over 24h using an intravenous catheter.
The volunteers will be discharged and followed up on Day 3 for routine blood tests. The washout period will be > 7 days from the first dose of PQ and subjects will be readmitted for the second round of dosing with the other PQ formulation. Follow up will also be on Day 3 of round 2.
Plasma samples will be analysed and the key pharmacokinetic parameters (Cmax , AUC0-t , AUC0-∞) for determining bioequivalence will be assessed by non-compartmental analysis.
WHO Prequalification
The prequalification dossier will be submitted to WHO by IPCA with the support of the DPP consortium. This step will follow if the adult generic 15 mg scored tablet is confirmed to be bioequivalent to the Sanofi 15 mg reference tablet.
The 2.5 to 7.5 mg tablets will be designed with proportionally similar compositions to the reference 15 mg primaquine tablet. Pharmaceutical specifications and control tests on the finished products will be performed. Laboratory analyses will confirm the composition, potency and proportionality of all strengths.
If comparative in vitro dissolution profiles between the test and reference strengths show their equivalence, prequalification biowaiver dossiers for all lower strengths will be submitted to WHO by IPCA with the support of the DPP consortium.
Formulation & packaging
Taste-masking
This will be led by the Ecole de Biologie Industrielle in France and has two components, a non-clinical gustatory sensory test (GST) approach, followed by the acceptability study in the field validation trials.
Preliminary non-clinical gustatory sensory studies will save time and money to develop optimised flavoured primaquine formulation for a paediatric population.
Staged sensory studies will be conducted by expert panels to identify and select the best taste-masking aromas. The masking effect of the ingredient and the flavours will be validated by the low level of bitterness and analysed with a software such as Tastel® and “R”.
For the expert panels, primaquine will be replaced initially by another bitter agent e.g. caffeine or quinine that will be mixed with the exact ingredients found in IPCA’s primaquine tablet. Once selected, the taste masking properties of the aromas will be assessed with primaquine and the aroma that best masks primaquine’s taste will be selected so that optimal flavoured tablets of each strengths will be designed, and the clinical batches will be produced by IPCA for the field testing.
Granules
This work will be carried out by the LTPIB. Developing primaquine granules is a promising alternative to paediatric tablets and are considered to be the pharmaceutical form of choice for small children. Their flexibility allows them to be manufactured as a fixed mg dose / unit weight so that they can put in sachets containing a desired dose of primaquine.
Granulation is a process of size enlargement whereby small particles are gathered into larger, permanent aggregates. The process involves the agitation of moistened powders in a mixer, followed by compression, extrusion and globulation resulting in the granule of a desired size. Wet granulation is a standard process in which the properties of powders are improved to facilitate the manufacture of granules and tablets.
Working closely with the EBI team, taste-masked and tasteless formulations will be assessed.
Once the formulation has been optimised in the laboratory, the next step will be to transfer the technology to an industrial partner to scale up and produce clinical batches for further assessment. This will be a future project subject to obtaining funds.
Updates
Under the EDCTP2 grant, the preliminary development work on the granules has been completed and an advanced formula of primaquine granules has been prepared. However, additional work was required to obtain an optimised and stable formulation that could be scaled up for future trials in humans. Thanks to internal Oxford University funding obtained in 2022 by the coordinator through the Medical and Life Sciences Translational Fund, this work has been realised by performing additional taste masking studies to produce granules that are currently undergoing accelerated stability studies under tropical conditions (40 0 C, 75% humidity) and has also allowed Oxford University, MORU, ReMeD, LTPIB, EBI and UCL to continue their collaboration. The results will be known by September 2023 and if they confirm stability, we will be able to move forward with an industrial partner, provided additional funds can be obtained.
Blister packaging
LTPIB and ReMeD will discuss with Bilcare, our packaging partner, on optimal designs of blister packaging. Bilcare will then produce several blister prototypes that we will assess in the field for acceptability using a questionnaire and through focus group discussions.
The results from these assessments will inform the future design of the blister pack that will be made available for malaria control programmes.
Field validation
Radical cure
This will be a single arm observational study to assess the pharmacokinetic parameters, efficacy and tolerability of primaquine in Ethiopian paediatric patients (<16 y) with acute uncomplicated vivax malaria. All patients will receive chloroquine, dosed by weight, and primaquine will be dosed by weight, according to an optimised, allometrically scaled regimen designed by the MORU team with an adult target dose of 0.25 mg/kg/day x 14d (as per national guidelines). Follow up is six months.
Primaquine will be blister packed for each regimen with the requisite number of tablets at appropriate strengths i.e. one tablet / dose so no tablet fractions will be used. All drug doses will be administered by a team member. Patients will be screened initially for G6PD status using a reliable qualitative G6PD (Access BioCareStart™) rapid diagnostic test (LaRue, Kahn et al. 2014) (Roca-Feltrer, Khim et al. 2014) and, if deficient, they will be given weekly primaquine, 0.5 mg/kg/week x 7w (optimised and allometrically scaled).
Transmission blocking
This open randomised trial is assessing the pharmacokinetics, anti-infectivity efficacy and tolerability of single low dose primaquine (SLDPQ) in children < 5 years from Burkina Faso with acute uncomplicated P. falciparum.
Patients will receive artesunate pyronaridine + SLDPQ (target dose 0.25 mg/kg), both dosed by weight. The SLDPQ regimen will be allometrically scaled and developed by MORU. Infectivity will be assessed by direct membrane feeding assays on D0, D2, D3, D7 & 14. We will not screen out G6PDd patients because evidence suggests good SLDPQ tolerability in G6PD deficient patients (Taylor, unpublished). Follow up is for six weeks (D42). The primary end point is mosquito infectivity on D2, defined as the difference in proportions of patients infecting ≥1 mosquito in the 2 arms (Dicko, Brown et al. 2016).
Acceptability
The acceptability studies of the flavoured tablets versus the basic formulation will be conducted in Ethiopia and Burkina Faso and will be nested in the two validation field trials. The acceptability study will be assessed using CAST (ClinSearch Acceptability Score Test), a tool developed by EBI’s partner ClinSearch (Ruiz, Vallet et al. 2017). It is based on a questionnaire that includes elements such as the child’s reaction in accepting the drug, result of the intake (how much of the dose was taken), methods used to achieve taking the drug (e.g. food, drink, restraint), and time taken to administer the primaquine.
In Ethiopia, three tablets will be used: the standard bitter tablet, and two flavoured tablets and the acceptability scores will be compared between the standard and flavoured tablets. In Burkina Faso, only flavoured primaquine tablets will be used and their CAST score will be compared to that of the artesunate pyronaridine granules. CAST scores will be analysed visually positioning of the different paediatric formulations on a four clustered acceptability map, to define a centroid and a 95% confidence ellipse and the profiles ranked.
Several prototype blisters will be presented to patients and assessed using a scoring system (to be developed) including blister size, colour, ease of use, font of the printed text and ease at distinguishing which blister for which weight range. The sample size for this exploratory study is 50 patients or guardians per country; total 100.
Socioeconomic aspects
Both field clinical studies will also include a socioeconomic component e.g. knowledge, attitudes and practice survey on malaria and health seeking behaviour, focused group discussions on improving health in the community with the use of drugs that have community rather than an individual benefit, and willingness to pay etc.
Communication, Dissemination & Exploitation
Communication strategy
The DPP project is designed to have an international impact, so timely communication and dissemination and exploitation of the results are important elements.
The website will be the face of the project and will serve as its information hub. Periodic updates will keep our audience abreast of new developments and outcomes and sustain a growing interest in our work and malaria issues more broadly. The website is designed for a wide audience from those who are curious about malaria elimination to policy makers. The web site is written in English and French to extend our reach.
Social networks are now well established as means of rapid communication to a global audience. Accordingly, we have a LinkedIn page (www.linkedin.com/company/dpp-consortium) and a Twitter account (@DPP_consortium) that will allow us to follow key individuals and organisations from the world of malaria, other neglected tropical diseases (NTD), and paediatric formulation development. Via LinkedIn, we have already been contacted by a group managing a consortium for another NTD.
The scientific content of the DPP project demands that we adopt an energetic approach to publishing our data in a timely fashion in peer reviewed journals and presenting our results at international and EDCTP meetings and to malaria control programmes. In this way, we will be contributing new evidence on primaquine for malaria elimination and engaging directly with policy makers. This will lay the groundwork when, in partnership with WHO prequalification, we register primaquine in endemic countries. We are already working with the prequalification team study and this channel of communication will grow as the project takes off and the prequalification dossier is assembled.
One important theme of our project is making primaquine globally available as a public good. By publishing the results of the taste masking studies and the pharmaceutical content of primaquine, other manufacturers can step in and produce their brand of primaquine and keep its price competitive.
It is essential that we feed back our results to the communities where we have conducted our research. In addition, we plan a programme of community engagement utilising ReMeD’s network of pharmacists and other stakeholders that are involved in the supply of essential medicines in Africa.
Capacity building
The ambitious and demanding development plan will not only be a learning experience for all partners but will also provide valuable opportunities for young African scientists to gain an insight in drug development and pursue PhDs and MSc degrees. Integrated within the project, will be inhouse training programme on key aspects of this project that will be study specific (e.g. clinical aspects of G6PD deficiency) and generic GCP and ethics led by MORU and the partners.
All studies will be conducted according to ICH GCP and following the Principles of Helsinki (2013 update). Ethical approvals will be obtained from all national ethical committees and regulatory bodies, as required.
We will have a good system of quality control in place for all of the studies and will pay extra attention to the demands of the bioequivalence study to meet WHO standards. Monitoring will be conducted by MORU and IPCA will be actively involved in the bioequivalence study.