dihydroartemisinin/ piperaquine efficacy and safety in ... · what was known regarding dha/pqp? •...

DIHYDROARTEMISININ/ PIPERAQUINE EFFICACY AND SAFETY IN DIFFERENT ETHNICITIES

QUIQUE BASSAT CRESIB (Barcelona Centre for International Health Research)

Hospital Clinic/University of Barcelona, Spain

O

OH

O

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H

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OR

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Some history

• Piperaquine developed in China where in

1978 it replaced chloroquine as 1st line

treatment

• Extensively used in MDA there until

abandoned due to the appearance of

resistance

• DHA is the active metabolite of the more

widely used artesunate and artemether.

Developed also in China

What was known regarding DHA/PQP?

• Efficacy over 28—63 days exceeded 95%

• Tolerability uniformly good

• No serious adverse effects identified

Review of 14 studies on 2,636 patients in Southeast Asia and

Africa, mostly adults

What was then needed?

A GMP product that could be studied under GCP in

the following ethnic groups:

• Children from Africa, the primary target

population

• Adults from South East Asia

African trial: 5 countries

301 patients

278 patients

223 patients

447 patients 304 patients

Art/Lum (6-dose regimen):

Day 1 Day 2 Day 3

0 8 Morning Afternoon Morning Afternoon

A large, open label, randomised clinical trial (~1500 children, < 5 years), to

assess DHA/PQP non-inferiority vs. AL

African Study outline

DOSING FOR A CHILD OF 20 Kg

DHA/PQP (3-dose regimen)

Day 1 Day 2 0 24 hours 48 hours

Clinical trials unit in Manhiça, Mozambique

DHA/PQP

AL

In infants, PCR-corrected cure rates > 90% and similar between groups

DHA/PQP is not inferior to AL

p<0.001

97.5%CI>7.6

p=NS

97.5%CI> -3.0

Per Protocol

DHA/PQP protects against new infections

A large, open label, randomised clinical trial (~1150 patients, including

children), in Laos, Thailand, and India to assess DHA/PQP non-inferiority vs.

AS+MQ

Asian Study outline

DHA+PQP (3-dose regimen)

24 48 0

AS + MQ (3-dose regimen)

0 24 48

DOSING FOR A PATIENT OF 40 Kg

75.5

66.4

98.7 97.0

50

60

70

80

90

100

uncorrected cure rate PCR-corrected cure rate

Per Protocol

p=0.002

CI > 3.1%

AS/MQ DHA/PQP

DHA/PQP is not inferior to AS+MQ

p=NS

CI > -0.4%

DHA/PQP protects against new infections

4ABC Trial: the largest non-sponsored DHA-PQP study

• Multicentre (7 countries)

randomised, open label

• Enrolled over 5000 patients

• ACTs: AL, AS/AQ, CDA and

DHA/PQP

• Children: 6-59 months

• Primary endpoint: d28 PCR

corrected ACPR

• CDA arm stopped earlier; in relation to safety concerns from

other trials but also because of its clear lowest efficacy

• AL, ASAQ and DHA/PQP well tolerated, and with few SAEs

• 13 deaths during the 6 month long follow-up, none related to

treatment

Summary of safety and tolerability

Cure rates D28 (uncorrected) Cure rates D28 (corrected)

DHA/PQP was not inferior to other ACTs

Days from start of treatment

Pro

babili

ty tre

atm

ent fa

ilure

fre

e

ASAQ

DHA-PQP

AL

CD+A

0 7 14 21 28 35 42 49 56 63

0.0

0.2

0.4

0.6

0.8

1.0

Treatment failure until Day 63

Proportion of treatment failure free by day of follow up

(ITT population, pooled data over all sites)

DHA/PQP

DHA/PQP PK profile is similar in different ethnic groups

PQP DHA

Asians vs. Caucasians

Conclusions

DHA/PQP

• Is non-inferior to other ACTs

• Is superior to other ACTs in preventing new infections

• Has repeatedly shown good tolerability and safety as other ACTs

• Has simple dosing enhancing adherence

• Does not need a fat meal to increase bioavailability

Thank you!