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A Phase IIa Clinical Trial of 2-Iminobiotin for the Treatment of Birth Asphyxia in DR Congo, a Low-Income Country

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Abstract

Aim

The main burden of hypoxic-ischemic encephalopathy falls in low-income countries. 2-Iminobiotin, a selective inhibitor of neuronal and inducible nitric oxide synthase, has been shown to be safe and effective in preclinical studies of birth asphyxia. Recently, safety and pharmacokinetics of 2-iminobiotin treatment on top of hypothermia has been described. Since logistics and the standard of medical care are very different in low-resource settings, the aim of this study was to investigate safety and pharmacokinetics of Two-IminoBiotin in the Democratic Republic of Congo (TIBC).

Methods

Near-term neonates, born in Kinshasa, Democratic Republic of Congo, with a Thompson score ≥ 7 were eligible for inclusion. Excluded were patients with (1) inability to insert an umbilical venous catheter for administration of the study drug; (2) major congenital or chromosomal abnormalities; (3) birth weight < 1800 g; (4) clear signs of infection; and (5) moribund patients. Neonates received six infusions of 2-iminobiotin 0.16 mg/kg started within 6 h after birth, with 4-h intervals, targeting an AUC0–4h of 365 ng*h/mL. Safety, defined as vital signs, the need for clinical intervention after administration of study drug, occurrence of (serious) adverse events, and pharmacokinetics were assessed.

Results

After parental consent, seven patients were included with a median Thompson score of 10 (range 8–16). No relevant changes in vital signs were observed over time. There was no need for clinical intervention due to administration of study drug. Three patients died, two after completing the study protocol, one was moribund at inclusion and should not have been included. Pharmacokinetic data of 2-iminobiotin were best described using a two-compartment model. Median AUC0–4h was 664 ng*h/mL (range 414–917). No safety issues attributed to the administration of 2-iminobiotin were found.

Conclusion

The present dosing regimen resulted in higher AUCs than targeted, necessitating a change in the dose regimen in future efficacy trials. No adverse effects that could be attributed to the use of 2-iminobiotin were observed.

EudraCT number 2015-003063-12.

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Acknowledgements

We greatly thank Laurent Favié and Floris Groenendaal, the investigators of the 2-STEP study, who included patients in the 2-STEP study and provided PK data of patients from Group A to enrich the PK population model.

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Authors and Affiliations

  1. Neonatal Unit, Department of Pediatrics, University Hospital of Kinshasa, Kinshasa, Democratic Republic of Congo

    Thérèse Biselele, Jephté Bambi, Dieu M. Betukumesu & Yoly Ndiyo

  2. Neonatal Unit, Department of Pediatrics, Clinique Ngaliema, Kinshasa, Democratic Republic of Congo

    Gabriel Tabu & Josée Kapinga

  3. Neonatal Unit, Department of Pediatrics, Hôpital Saint Joseph, Kinshasa, Democratic Republic of Congo

    Valérie Bola & Pascal Makaya

  4. Neurophyxia BV, Onderwijsboulevard 225, 5223 DE, ’s-Hertogenbosch, The Netherlands

    Huibert Tjabbes & Cacha Peeters-Scholte

  5. LAP&P Consultants, Leiden, The Netherlands

    Peter Vis

Authors
  1. Thérèse Biselele
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  2. Jephté Bambi
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  3. Dieu M. Betukumesu
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  4. Yoly Ndiyo
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  5. Gabriel Tabu
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  6. Josée Kapinga
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  7. Valérie Bola
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  8. Pascal Makaya
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  9. Huibert Tjabbes
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  10. Peter Vis
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  11. Cacha Peeters-Scholte
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Corresponding author

Correspondence to Cacha Peeters-Scholte.

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Funding

This study was funded by Neurophyxia BV.

Conflict of interest

Authors T. Biselele, J. Bambi, D. Betukumesu, Y. Ndiyo, G. Tabu, J. Kapinga, V. Bola, P. Makaya, and P. Vis have no disclosures. Authors H. Tjabbes and C. Peeters-Scholte are co-founders, consultants for and shareholder of Neurophyxia BV. Author H. Tjabbes is Vice-President Regulatory and Medical Affairs of Neurophyxia, and author C. Peeters-Scholte is Chief Scientific Officer.

Informed consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethical committee of the Public Health School of the University of Kinshasa (DR Congo) and the ethical committee of the University of Utrecht (The Netherlands), and in line with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from one of the parents in local language (Lingala) or French before start of the study. When the consenting parent was illiterate, informed consent was given verbally in the presence of an impartial witness.

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Biselele, T., Bambi, J., Betukumesu, D.M. et al. A Phase IIa Clinical Trial of 2-Iminobiotin for the Treatment of Birth Asphyxia in DR Congo, a Low-Income Country. Pediatr Drugs 22, 95–104 (2020). https://doi.org/10.1007/s40272-019-00373-3

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  • DOI: https://doi.org/10.1007/s40272-019-00373-3

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