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Efficacy and safety of injectable quinine in malaria patients (Injectable quinine for malaria)

Treatment of severe malaria with injectable quinine (Injectable quinine for malaria)

28

Country of origin: Japan (n = 21) and other countries (n = 7), including Fiji (n = 1), Uganda (n = 1), Kenya (n = 1), Cameroon (n = 1), Poland (n =1), and Nigeria (n = 2). Age: 6-72 years (mean, 44.5 years; median, 43.5 years). Sex: Male (n = 18) and female (n = 10). Estimated place of infection: Sub-Saharan Africa for all cases.

Study periods and number of participants Guideline period: June 16, 2017 -March 18, 2019: 9 participants Specified Clinical Study (per year): Year 1 (March 19, 2019 -March 18, 2020): 5 participants Year 2 (March 19, 2020 -March 18, 2021): 1 participant Year 3 (March 19, 2021 -March 18, 2022): 4 participants Year 4 (March 19, 2022 -March 18, 2023): 2 participants Year 5 (March 19, 2023 -March 18, 2024): 3 participants Year 6 (March 19, 2024 -March 18, 2025): 2 participants Year 7 (March 19, 2025 -March 18, 2026): 2 participants Year 8 (March 19, 2026 -June 20, 2026): 0 participants

Unexpected Adverse Drug Reactions Serious: 0, Non-serious: 0 Expected Adverse Drug Reactions Serious: 0, Non-serious: 53 events (21 participants) Adverse Events (related to the underlying severe malaria) Deaths: 3 participants Serious: 17 events (10 participants) Non-serious: 30 events (16 participants) The most frequently reported adverse drug reaction was hemolytic anemia, which was considered an inevitable consequence of the therapeutic effectd of intravenous quinine, thus its occurrence was inevitable. Other frequently reported adverse reactions included QT prolongation, hypoglycemia, nausea, vomiting, and hearing impairment or tinnitus, all of which were well-known adverse effects of quinine. Among the six participants who developed QT prolongation, quinine administration was quited in two participants. Both were switched to oral antimalarials, after which parasitemia cleared and no recrudescence was observed.

Primary endpoint: survival rate at 4 weeks after treatment Among the 28 participants who were treated, the mean interval from symptom onset to initiation of intravenous quinine was 4.4 days (range 1-10 days; median 4 days). The number of quinine injections ranged from 1 to 15 (mean 6.4; median 6). After completion of intravenous quinine, oral antimalarials were administered; Riamet (artemether-lumefantrine) in 18 participants, Malarone in 1 participant, a combination of Riamet and Malarone in 3 participants. No oral medicines were administered in 4 participants (including 2 deaths). In cases of vivax malaria, radical cure with primaquine was given after acute-phase treatment. Outcomes were 25 participants cured and 3 deaths, resulting in an overall survival rate of 89.3 % (95 % confidence interval 71.8-97.7). A Z-test yielded a two-sided p-value of 0.17 and a one-sided p-value of 0.084, indicating that the observed survival rate did not significantly differ from the expected 95% at a 5% significance level. Secondary endpoints 1) Parasite Clearance Time At enrollment, parasitized red blood cell counts ranged from 8,240 to 980,100 /uL (median 344,225/uL ). Intravenous quinine rapidly reduced parasitemia, falling below the detection limit within 3-11 days (median 5.0 days). Even in participants who could not be rescued, parasitemia decreased rapidly. Some participants could not be followed until Day 28 due to leaving Japan, however but no recrudescence occurred in followed participants. 2) Fever Resolution Time Enrollment body temperature ranged from 36.6C to 40.7 C (median 37.9 C). Most participants became afebrile after quinine treatment. Some participants, particularly those who died, experienced prolonged or recurrent fever, likely due to treatment-associated hemolytic anemia or excessive macrophage activation. Time to fever resolution ranged from 1 to 22 days (median 5.5 days). 3) Recrudescence until Day 28 Among 23 participants who could be followed until Day 28, no recrudescence was observed. The remaining 5 participants included 2 who discontinued follow-up due to leaving Japan (1 Fijian and 1 Japanese) and 3 deaths.

Intravenous quinine rapidly cleared parasitized red blood cells from the peripheral blood, and the primary endpoint-survival rate at 4 weeks after treatment-was 89.3% (25/28). This outcome is comparable to results from large-scale studies conducted in Southeast Asia and Africa, demonstrating that intravenous quinine is an effective treatment for severe malaria in Japan as well.

April. 30, 2026

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs071180063

Maruyama Haruhiko

University of Miyazaki Hospital

5200 Kihara, Kiyotake, Miyazaki 889-1692, JAPAN

hikomaru@med.miyazaki-u.ac.jp

Maruyama Haruhiko

University of Miyazaki

5200 Kihara, Kiyotake, Miyazaki 889-1692, JAPAN

+81-985-85-0990

hikomaru@med.miyazaki-u.ac.jp

Complete

June. 16, 2017

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Severe malaria patient, or malaria patient who cannot take oral antimalarial medicines for absolute contraindication or other reasons
2) Patient who gives written informed consent on his/her own free will to participate the above described study, after having fully understood the explanations on it
3) Patient whose legal representative gives written informed consent on his/her own free will to let the patient participate the above described study, after having fully understood the explanations on it

1) Patient who is allergic to quinine
2) Patient who refuses quinine injection
3) Patient principal investigator judged inappropriate

Both

malaria

Treatment with un-licensed medicine

survival rate

1) Fever clearance time (h)
2) Parasite clearance time
3) Recrudescence before 28 days post-treatment

+81-92-643-7171

Oct. 11, 2018

none