Roadmap


The DPP project has three main elements

Roadmap 1

1

Developing quality-assured primaquine tablets through the WHO pre-qualification scheme

The prequalification pathway will start with prequalifying a scored generic 15 mg primaquine tablet by performing a bioequivalence study against the Sanofi reference primaquine (15 mg). Assuming bioequivalence is confirmed, a dossier will be prepared and submitted to the WHO.

Lower tablet strengths of 2.5, 3.75 and scored 5 & 7.5 mg will be produced and also prequalified, under what is referred to as a “line extension.” The line extension is based on demonstrating proportionality with the 15 mg adult tablet so that we can apply for a biowaiver. This means bioequivalence studies of each lower tablet strength are not required.

Roadmap 2

2

Improving the basic dosage form to become child-friendly to enhance its acceptability and adherence to treatment (formulation & presentation)

The current primaquine formulation will be improved by developing :

  • a primaquine taste-masking aroma
  • bespoke blister packaging
  • granules as a new child-friendly dosage form

Sensory (i.e. taste masking) studies will be performed at an early stage to identify the best aromas to mask the bitter taste of primaquine, followed by a field-based assessment of the acceptability of the flavoured tablets and the different prototypes of blister packaging.

Preliminary work on developing quality-assured granules will be followed by a grant application to produce and test a clinical batch with a view to prequalification or registration.

Roadmap 3

3

Validate the new primaquine paediatric tablets in the field, by assessing :

  • their efficacy and tolerability as radical cure of 14-day primaquine in vivax-infected patients in Ethiopia
  • transmission blocking efficacy and tolerability of single low dose primaquine in falciparum-infected children < 5 years in Burkina Faso
  • their acceptability by children and care givers e.g. the tablets in multiple strengths, taste (flavoured vs. basic tablets) and packaging.

Cross-cutting themes

Two important underlying themes of this project are developing quality-assured child-friendly primaquine as a public good and at an affordable price and capacity building that will include inhouse training on regulatory processes, ethics, and GCP and encouraging young scientists to undertake MSc and PhD degrees.

Post WHO prequalification, IPCA will register primaquine starting with endemic countries that are part of the WHO accelerated registration process, and the consortium together with IPCA will develop a post-registration marketing strategy to engage with Malaria Control Programmes and conduct post marketing pharmacovigilance.

We will develop a comprehensive communication strategy.

Workplan


The workplan is organised under three activities and seven work packages. Within these, partners have well-defined roles with deliverables and milestones :

PERT Chart

DPP project : PERT Chart

Work packages 1-3 comprise the clinical studies of the project and the two field trials will validate the primaquine tablets and regimens and aim to make globally available quality-assured, optimised primaquine regimens to treat malaria in the short to medium term. By contrast, WPs 4 & 5 aim to prepare better child-friendly formulations and presentation.

Clinical trials

WP1

Bioequivalence (BE) study

+ Open description

WP1 : The BE study is a classic two way cross over study with 50 healthy subjects. We will use a scored generic 15 mg tablet of primaquine, produced by IPCA, and test it against the Sanofi 15 mg tablet; the wash out period is at least 7 days. The data from this study will be used in the WHO dossier so that the adult 15 mg tablet can be prequalified. The dossier will be assembled by IPCA who will also apply for biowaivers for the lower tablet strengths. The BE study represents a core activity of this project with all the other studies linked to it.

WP2

Radical cure (RC) study

+ Open description

WP2 : This is a field trial of children with vivax malaria using the IPCA produced primaquine of all strengths. The primaquine regimen will be allometrically scaled and the pharmacokinetic (PK), efficacy and tolerability data will confirm (or otherwise) that our regimen is correct. Blister-packed, unflavoured and flavoured tablets will be used for the acceptability assessment.

WP3

Transmission blocking study

+ Open description

WP3 : Similar to WP2, we will assess, in falciparum-infected children < 5y, an allometrically scaled regimen of single low-dose primaquine and its anti-infectivity efficacy, as the pharmacodynamic (PD) marker. We plan to use flavoured 2.5 and 3.75 mg tablets and assess drug acceptability. Again, the PK data and PK PD analysis should confirm that the primaquine dose is scientifically sound.

Formulation

WP4

Contextualisation : aroma selection & acceptability

+ Open description

WP4 : This WP has the important aim of ensuring we find the best flavours to mask the bitterness of primaquine; the selection will be done in adult volunteers first before they are tested in the two field trials. EBI will oversee these studies, design the questionnaires for the volunteer studies and field trials, and analyse the data.

WP5

Conceptualisation : granulation & packaging

+ Open description

WP5 : This WP, led by LTPIB, is to conduct the preliminary work on a granule formulation that could then be taken up by an industrial partner for future development as flavoured granules that would then be formally tested in patients to assess acceptability, efficacy, tolerability and pharmacokinetic characteristics (this will require more funds and be subject to another funding application).

LTPIB will also work with IPCA, Bilcare and the field teams on designing blister prototypes for their assessment of acceptability in both field trials. EBI will help design the acceptability questionnaire and analyse the data.

Both aspects of WP5 are important for finding acceptable primaquine formulations and presentations to enhance adherence to treatment.

Administration

WP6

Consortium Management

+ Open description

WP6 : Good project management is fundamental to the success of this project and keeping the project moving forward in a cohesive way. This WP includes several key aspects:

  • project organisation and governance bodies
  • project management and oversight
  • study quality management
  • primaquine PK analysis
  • data management
  • statistics
  • communication

WP7

Communication, dissemination & exploitation

+ Open description

WP7 : This work package covers the important elements of communication, dissemination and exploitation. Our communication and dissemination plans are closely interlinked so we can reach a wide audience, both scientific and lay and inform them of the merits of the project, its results and impact. Publishing in peer-reviewed journals and presentations at the EDCTP fora and international conferences are not only important aspects of communication and dissemination but will also be a good way to build capacity and confidence in our junior members.

Timelines


SEPTEMBER 2020

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Start of the project

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DECEMBER 2020

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Kick off meeting

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JANUARY 2021

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Start of clinical trials preparation work

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AUGUST 2021

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Primaquine taste-masking aroma validated

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DECEMBER 2021

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Granule formulation finalised

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2022

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Clinical trial recruitment starts

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In terms of timelines, several activities can commence in parallel, notably the granulation work (LTPIB) and preparations for the sensory (EBI), bioequivalence (AHRI) and field (AHRI & GRAS) studies, and discussions on blister pack design (in association with Bilcare).

The sensory studies are overseen by EBI and will be the first studies to start. These will be followed in sequence by the BE study and the field trials. These latter studies depend on the availability of the clinical batches which IPCA will produce. The estimated dates for the exhibit batches to be ready were initially May 2021 for the standard adult dose (15 mg) and the lower tablet strengths, but with the world pandemic situation are now postponed to early September. These timelines mean that the BE and field trials will start in December 2021 and January 2022, respectively.