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The efficacy of Artesunate rectal suppositories
Leonard Sacks
Medical Officer
CDER. FDA
2
FDA Review Team forNDA 21-242
• Regulatory Project Manager:
• Chemistry Reviewer:
• Microbiology Reviewer:
• Biopharmacology/BiopharmaceuticsReviewer
• Pharmacotoxicologist Reviewer:
• Statistical Reviewer:
• Medical Reviewers:
M. Bacho, B.S.
J. Smith, Ph.D.; D. Cummings
K. Suvarna, Ph.D.
J. Meyer, Pharm. D.
S. Kunder, Ph.D.
R. Davi, M.S.
L. Sacks, MB.B.Ch.
R. Johann-Liang, M.D.
3
Background
4
Rationale for product development
• High mortality from malaria, especially in children, due to delays in therapy
• Malaria patients often unable to take orally
• Parenteral therapy not available in the bush
5
Goal of applicant
• To develop an effective antimalarial that:– can be administered rectally– serves as an emergency treatment until
definitive therapy can be reached – that decreases malaria mortality and morbidity
6
Indication
• For the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available
• …..must be supplemented and/or followed by effective oral or parenteral drug therapy for malaria as soon as possible
7
Rectal artesunate- a suitable candidate?
• Artemisinin derivatives are potent antimalarials
• Used successfully in areas of drug-sensitive and resistant P falciparum
• Short half life • Associated with
recrudescence• Potential neurotoxicity
8
Clinical pharmacologyAdult healthy subjects, 400-mg single dose
Analyte Tmax (hours) Cmax
(ng/mL) T1/2
Artesunate 2.37 0.30 261 170 < 3 hours
DHA
3.32 0.21 399 240 < 3 hours
Artesunate is rapidly biometabolised to dihydroartemisinin (DHA)
Dihydroartemisinin is also active against P falciparum
9
Clinical pharmacology
• In the course of product development, the formulation used in clinical trials and the formulation to be marketed were different.
10
Bioequivalence between formulation in clinical trials and formulation to be marketed
• Bioequivalence study in healthy volunteers failed to satisfy regulatory requirements– Point estimates of AUC and Cmax were similar but 90% confidence intervals
were too wide
• variablity due to difficulties in plasma measurement
• inter- and intra- subject variability in absorption, distribution, metabolism and elimination
• Study lacked adequate power to demonstrate tighter confidence intervals
• Equivalence study with clinical endpoints (014) in malaria patients showed similar parasite clearance at 24 hours
11
Bioequivalence between formulation in clinical trials and formulation to be marketed
(cont.)
• “totality of the data”– technical difficulties and intra-subject
variability in measurement, – satisfactory clinical performance of
to-be-marketed product in 014 – potential use for life threatening illness, where
alternative treatment unavailable
12
Challenge to develop appropriate clinical studies
Prior to definitive treatment, is the emergency use of a single dose of rectal artesunate more effective than no treatment in reducing malaria morbidity and mortality?
13
Challenge to develop appropriate clinical studies
• Given the high mortality from untreated malaria and the dangers of delaying effective therapy, treatment cannot be ethically withheld for the first 24 hours if effective therapy is available.
• For these reasons, the clinical trials submitted in this NDA have employed active comparators.
• In these studies, provisions are made for the “rescue” of patients showing an unsatisfactory clinical or parasitological response.
• While these studies do not directly address the advantages of rectal artesunate over no treatment, they give a relative idea of efficacy versus the “standard of care”.
• A trial (study 13) is underway to investigate the product under conditions that more closely reflect the intended use. This trial has not been submitted to FDA.
14
Other problems in modeling the projected use
Clinical studies
• Most lived in malaria areas - some immunity
• Diagnosis was confirmed on smear
• Moderately severe (entry parasitemia…)
• Patients were hospitalized
Projected use
• May be used in US travelers and residents of malaria areas
• Diagnosis will not be confirmed before treatment
• All degrees of severity
• Not hospitalized
15
Other problems in modeling the projected use (cont’d)
Clinical studies
• Ancillary treatment provided (fluids, glucose anticonvulsants, antipyretics etc)
• Suppository retention was supervised
• Patients failing on parasitological grounds were rescued
• Definitive therapy provided at 24 hours
Projected use
• No ancillary treatment available in the field
• Retention may be supervised
• No rescue in the field
• Access to definitive treatment depends on local infrastructure
16
Selection of endpoints
• Mortality is not a realistic study endpoint– deaths are very rare in patients with moderately
severe malaria who are properly treated
• Alternative endpoints– response in parasitemia – clinical responses – rates of recrudescence
17
Studies of efficacy
NDA 21-242
18
Overview of clinical studies• Pivotal studies 005, 006, 007
– Comparative, randomized, unblinded– Employed projected dose for first 24 hours
• Bioequivalence study 014– Compared 3 formulations of rectal artesunate,
in projected dosing regimen
19
Overview of clinical studies(cont’d)
• Supportive studies 003, 004– Crossover/dose escalation studies comparing
rectal and intravenous artesunate over 12 hours
• Previous published studies 010, 011, 012– Employed twice the recommended dose- did
not support efficacy of the projected dose
20
Drug regimens in pivotal studies Thailand (005) Malawi (006) South Africa (007)
Experimental arm
Rectal AS (10mg/kg) single dose
Rectal AS (10mg/kg) single dose
Rectal AS (10mg/kg) single dose
Comparator Oral AS (4 mg/kg) single dose
Quinine 10mg/kg IM or IV at 0, 4 hrs then 12 hourly till oral treatment tolerated
Quinine 10mg/kg IM or IV at 0, 4 and 12hrs
Consolidation regimen
24 hrs: Oral AS (2mg/kg) 48 hrs: Oral AS (2mg/kg) + MQ (15mg/kg) 72 hrs: Oral AS (1mg/kg) + MQ (10mg/kg) Daily for 6 more days: Oral AS (1mg/kg)
24 hrs: Oral SP (25mg/kg SDX) (or “standard dose” parenteral quinine if unable to take orally) SP given at 24 hours in experimental arm SP given after a minimum of 2 doses of quinine in comparator arm
24 hrs: Oral SP (3 tablets) single dose (or IM quinine 10mg/kg if unable to take orally)
AS = artesunate
SP = sulfadoxine/pyrimethamine
MQ = mefloquine
21
Comment on study drugs• Quinine
– generally given for 7 days– 24 hours is inadequate and on its own would result
in recrudescences
• Sulfadoxine/pyrimethamine (SP)– a long-acting agent given as a single dose– SP resistance >60% in parts of Africa
22
Comment on study drugs(cont’d)
• Mefloquine– a long-acting agent, may be given as a
single dose– used effectively with artemisinins for
treatment of drug-resistant malaria
23
Inclusion and exclusion criteriaLocation (Study No.)
Thailand (005) Malawi (006) South Africa (007)Age 6 months-15 years 1 – 10 years 16 years – 65 yearsEligibleparasitemia(P falciparum)
>4% (200,000/ l) >0.4% (<20,000/ l) -
Clinicaleligibility
- Unable to eat or drinkorImpaired consciousness
Unable to eat or drink
Diarrhea Diarrhea DiarrheaUnable to eat or drink - -Previous antimalarial inpast 24 hrs
Previous antimalarial inpast 24 hours
Previous antimalarial inpast 24 hours
Severe malaria: Acidotic Hct < 15% Jaundice Bleeding Shock Decreased
consciousness
Severe malaria: Deep breathing Hct < 18% Jaundice Bleeding Shock Stupor or coma Convulsions
Severe malaria: Respiratory distress
Jaundice Bleeding Shock Coma >1 Convulsion Renal failure Hypoglycemia Lactate < 5 mmol/l
Exclusion
Parasitemia >20% Parasitemia >10% Parasitemia >10%
24
Baseline characteristics Location (Study No.) Thailand (005) Malawi (006) South Africa (007)
Number of patients Artesunate Comparator
46 17
87 22
27 8
Mean Age Artesunate Comparator
7 years 7 years
4 ½ years
4 years
29 yrs 25 yrs
% Males
63.5% 61.5% 51%
Entry parasitemia Artesunate Comparator
Median 245,366 376,649
Median 183,390 230,739
Median 51,240 58,340
Platelet count Artesunate Comparator
Median 85,000
129,000
Geom mean 74,500 67,000
Median 80,000 38,500
25
Criteria for providing rescue therapy
A parasite density 60% of the admission parasite density after 12 hours.
Clinical deterioration with the development of features of severe malaria, repeated convulsions or coma.
Thailand (005) Malawi (006) South Africa (007) Rescue in both arms Rescue only in rectal
artesunate arm Rescue in both arms
26
FDA-defined study endpoints
24-hour clinical success All treated patients: who were evaluated after 24 hours on study drug who had not received rescue therapy or alternative
antimalarial therapy who neither died nor deteriorated clinically since the
baseline evaluation24-hour parasitologicalsuccess
All 24-hour clinical successes whose 24 hour parasitecount was 10% of the baseline count
28-day recrudescence/re-infection
Any patient who received study drug and was found tohave a recurrence of parasitemia between the time thattherapy was stopped and day 28.
WHO primary endpoint was fractional remaining parasite count at 24 hours
27
Study-related events with an impact on clinical results
Location (Study No.)
Thailand (005) Malawi (006) South Africa (007)
Number of patients Artesunate Comparator
46 17
87 22
27 8
Exclusions Artesunate Comparator
5 3
3 0
1 1
Rescued for 12 hour parasitemia 60% of baseline
Artesunate Comparator
7 4
3
0 ( no provision for rescue)
1 2
Clinical deterioration Artesunate Comparator
1 0
4 0
0 0
Death Artesunate Comparator
1 0
0 0
0 0
Other failures Artesunate Comparator
1 (expelled supps)
N/A
1
N/A
0 0
28
24-hour clinical success
76%71%
91%100% 96%
75%
0%
10%20%
30%
40%
50%60%
70%
80%90%
100%
Thailand Malawi South Africa
ArtesunateComparator
29
24-hour parasitological success
76%71%
88%
14%
85%
25%
0%
10%20%
30%
40%
50%60%
70%
80%90%
100%
Thailand Malawi South Africa
ArtesunateComparator
30
28-day recrudescences/new infections
0% 0%
45%
23%
4%0%
0%
10%
20%
30%
40%
50%
Thailand Malawi South Africa
ArtesunateComparator
31
What can we conclude from pivotal studies?
• At 24 hours, the clinical success rates for rectal artesunate are similar to those seen with oral artesunate or quinine
• At 24 hours parasite clearance is significantly more rapid with rectal artesunate than with quinine.
• By 28 days, recrudescence rates are high when SP is used as definitive therapy.
• Recrudescence rates may be higher in artesunate-treated patients than in quinine-treated patients. This may depend on geographic location.
32
What can we not conclude from the pivotal studies?
• That we have characterized the impact of rectal artesunate on malaria mortality.
• That the same result will be seen in the field where hospitalization, supportive therapy and laboratory diagnostics are unavailable.
33
Equivalence study with clinical endpoints (014)
• Aimed to compare efficacy of – 2 x 200mg (used in clinical studies) – 4 x 100mg (to be marketed)– 1 x 400mg (to be marketed)
34
Treatment regimen (Study 014)
First 24 hours Rectal artesunate 400mg (singledose)
Follow-up Oral artesunate 200mg daily X 3Mefloquine 750mg daily X 2
35
Study population
• Thailand
• Hospitalized, adult patients
• Uncomplicated “moderately severe” malaria
• 23 patients per arm
36
Median parasite counts/μl following treatment with 3
formulations of rectal artesunate46720
30690
40680
3890
9980
13080
30 86 62 1 0 0
baseline 12 hours 24 hours 48 hours
2 x 200mg4 x 100mg1 x 400mg
37
Recrudescences/new infections?
38
Conclusion (study 014)
• Equivalent efficacy of the three formulations
• Also serves to demonstrate the non-comparative efficacy of rectal artesunate given alone for the first 24 hours to 69 adult patients with moderately severe, uncomplicated malaria.
• Among these 69 patients, none were judged by the study physicians to require rescue therapy.
• All made an uneventful clinical and parasitological recovery.
• Outcome beyond 7 days in these patients, in terms of recrudescence or new infection is not known.
39
Studies 003 and 004
• Crossover studies- rectal and IV artesunate at 2 doses
• “Moderately severe” uncomplicated malaria
• 003- hospitalized adults (Thailand)
• 004- hospitalized children (Ghana)
40
Studies 003 and 004 Location (Study No.) Thailand (003) Ghana (004)
IV AS 2.4mg/kg After 12 hrs, Rectal AS 10mg/kg
12 patients (Group 1) 0 patients
Rectal AS 10mg/kg After 12 hours IV AS 2.4mg/kg
12 patients (Group 2) 12 patients (Group 1)
IV AS 2.4mg/kg After 12 hrs, Rectal AS 20mg/kg
12 patients (Group 3) 12 patients (Group 3)
Rectal AS 20mg/kg After 12 hours IV AS 2.4mg/kg
12 patients (Group 4) 12 patients (Group 2)
41
“Consolidation therapy”
Location (Study No.) Thailand (003) Ghana (004) “consolidation therapy”
Mefloquine at 36 and 48 hours Chloroquine over 3 days (sulfadoxine-pyrimethamine if intolerant of chloroquine)
42
Study populations in 003 and 004
Thailand (003) Ghana (004) Inclusion criteria
Adults 16-50 years Children 18 months to 7 years Entry parasite count 100,000 / l Entry parasite count 10,000 / l Non per-os patient Non per-os patient No vital organ dysfunction
Exclusion criteria Cerebral malaria or complicated malaria (e.g. pulmonary edema, renal failure, shock)
Cerebral malaria (coma 2 on Blantyre scale) hypoglycemia, blood lactate 5 mmol/l or Hct < 15%
Rectal abnormalities/acute diarrhea Rectal abnormalities/acute diarrhea Previous antimalarial treatment
43
24-hour clinical success rate
Regimen Short term clinical successIV AS 2.4 mg/kg,Rectal AS 10 mg/kg
12/12
Rectal AS 10 mg/kg,IV AS 2.4 mg/kg
23/24
IV AS 2.4 mg/kg,Rectal AS 20 mg/kg
22/23
Rectal AS 20 mg/kg,IV AS 2.4 mg/kg
22/24 *
*In this treatment group, 2 patients progressed clinically to severe malaria
44
>90% clearance of baseline parasitemia at 12 and 24 hours
Regimen 12 hours 24 hoursIV AS 2.4 mg/kg,Rectal AS 10 mg/kg
1/12 8/12
Rectal AS 10 mg/kg,IV AS 2.4 mg/kg
5/23 21/23
IV AS 2.4 mg/kgRectal AS 20 mg/kg
5/23 20/22
Rectal AS 20 mg/kgIV AS 2.4 mg/kg
3/24 21/23 *
*In this treatment group, 2 patients progressed clinically to severe malaria
45
Recurrent parasitemia during 2-3 weeks after therapy
Recrudescence rate among patientsallocated to treatment
Mefloquine 7/48 15%Chloroquine 7/23 30%Sulfadoxine-pyrimethamine 2/9 22%
46
What did we learn from 003 and 004?
• No clinical advantage in using 20mg/kg rectal AS instead of 10mg/kg rectal AS
• Rapid reductions in parasitemia were confirmed
• Despite the 12 hourly regimen, recrudescence rates were still high
47
Summary• Among 229 evaluable patients with “moderately
severe” malaria treated with 10mg/kg rectal AS over first 24 hours– 1 death- (probable fluid overload)
– 24-hour clinical success rates similar to comparator
– 24-hour parasitological success superior to comparator
– 28 day recrudescence rates from 0-45% for rectal AS, 0-25% for comparator (follow-up rates were low)
48
Considerations
• Delays in therapy are one of the most important contributors to malaria mortality
• Given the potent effect on parasitemia, and the good short term clinical performance of rectal artesunate, does this imply that it will reduce malaria mortality?
• Are there potential hazards in the empirical use of rectal artesunate for emergency treatment?
49
Statistical issues
• In the evaluation of these studies there are difficulties in interpreting the parasitological responses, since failing patients were “rescued” from the analysis.
• Due to significant loss to follow up at later time-points, recrudescence rates may be inaccurate.
50
NDA 21-242 Rectal Artesunate
Ruthanna Davi, M.S.
Statistical Reviewer, FDA
51
NDA 21-242 – Rectal Artesunate
• Interpretation of Parasite Count Analyses in light of Rescued Patients
• Recrudescence with Artesunate
• Other risk factors for Recrudescence
52
Parasite Count Endpoint
• Numerical endpoints are statistically more sensitive than dichotomous endpoints.
• Excluding rescued subjects from the analysis is biased.
• Imputing values beyond the rescue time is biased.
• Ignoring the fact that subjects were rescued is biased.
53
Study 007: Parasite Count Across TimeRectal Artesunate Group
0
50000
100000
150000
200000
250000
300000
0 12 24
Time (hours)
Pa
ras
ite
Co
un
t
Study 007: Parasite Count Across TimeQuinine Group
0
50000
100000
150000
200000
250000
300000
0 12 24
Time (hours)
Pa
ras
ite
Co
un
t
Excluding RescuedExcluding RescuedArtesunate Subject, M34Artesunate Subject, M34
Excluding Rescued QuinineExcluding Rescued QuinineSubjects, M02 & M27Subjects, M02 & M27
Including RescuedIncluding RescuedArtesunate Subject, M34Artesunate Subject, M34
Including Rescued QuinineIncluding Rescued QuinineSubjects, M02 & M27Subjects, M02 & M27
Including (as LOCF) RescuedIncluding (as LOCF) RescuedArtesunate Subject, M34Artesunate Subject, M34
Including (as LOCF) RescuedIncluding (as LOCF) RescuedQuinine Subjects, M02 & M27Quinine Subjects, M02 & M27
54
Excluding RescuedExcluding RescuedArtesunate Subject, 6, 44,Artesunate Subject, 6, 44,57, 60, 70, 101, 104, &10557, 60, 70, 101, 104, &105
Protocol did not requireProtocol did not requireRescue of QuinineRescue of QuinineSubjectsSubjects
Study 006: Parasite Count Across TimeRectal Artesuante Group
0
100000
200000
300000
400000
500000
600000
700000
0 6 12 18 24
Time (hours)
Pa
ras
ite
Co
un
t
Study 006: Parasite Count Across TimeQuinine Group
0
100000
200000
300000
400000
500000
600000
700000
0 6 12 18 24
Time (hours)
Pa
ras
ite
Co
un
t
Including RescuedIncluding RescuedArtesunate Subjects; 6, 44,Artesunate Subjects; 6, 44,57, 60, 70, 101, 104, & 10557, 60, 70, 101, 104, & 105
Including (as LOCF) RescuedIncluding (as LOCF) RescuedArtesunate Subjects, 6, 44,Artesunate Subjects, 6, 44,57, 60, 70, 101, 104, & 10557, 60, 70, 101, 104, & 105
55
Excluding Rescued RectalExcluding Rescued RectalArtesunate Subjects, 2, 8, 14,Artesunate Subjects, 2, 8, 14,16, 18, 23, 36, & 4116, 18, 23, 36, & 41
Excluding Rescued OralExcluding Rescued OralArtesunate Subjects, 12, 32,Artesunate Subjects, 12, 32,38, & 6138, & 61
Study 005: Parasite Count Across TimeRectal Artesunate Group
0
100000
200000
300000
400000500000
600000
700000
800000
900000
0 12 24
Time (hours)
Pa
ras
ite
Co
un
t
Study 005: Parasite Count Across TimeOral Artesunate Group
0
100000
200000300000
400000
500000
600000700000
800000
900000
0 12 24
Time (hours)
Pa
ras
ite
Co
un
t
Including Rescued OralIncluding Rescued OralArtesunate Subjects, 12, 32,Artesunate Subjects, 12, 32,38, & 6138, & 61
Including Rescued RectalIncluding Rescued RectalArtesunate Subjects, 2, 8, 14,Artesunate Subjects, 2, 8, 14,16, 18, 23, 36, & 4116, 18, 23, 36, & 41Including (as LOCF) RescuedIncluding (as LOCF) RescuedRectal Artesunate Subject, 2,Rectal Artesunate Subject, 2,8, 14, 16, 18, 23, 36, & 418, 14, 16, 18, 23, 36, & 41
Including (as LOCF) RescuedIncluding (as LOCF) RescuedOral Artesunate Subjects, 12,Oral Artesunate Subjects, 12,32, 38, & 6132, 38, & 61
56
Parasite Count with Rescued Subjects Excluded
Median Fractional Remaining Parasite Count
Study 7 South AfricaN1=25, N2=4
Study 6 MalawiN1=75, N2=22
Study 5 ThailandN1=32, N2=10
12 hrs 24 hrs 12 hrs 24 hrs 12 hrs 24 hrs
RectalArtesunate
11.1% 0.6% 27.6% 0.1% 19.4% 0.0%
ComparatorQN or Oral AS
51.2% 27.8% 82.0% 59.2% 21.9% 0.0%
WilcoxonRank SumTest p-value
0.0047 0.0011 <0.0001 <0.0001 0.3083 0.3164
57
Parasite Count with Rescued Parasite Count with Rescued Subjects IncludedSubjects Included
Median Fractional Remaining Parasite Count
Study 7 South AfricaN1=26, N2=6
Study 6 MalawiN1=83, N2=22
Study 5 ThailandN1=40, N2=14
12 hrs 24 hrs 12 hrs 24 hrs 12 hrs 24 hrs
RectalArtesunate
11.9% 0.6% 27.7% 0.1% 23.5% 0.0%
ComparatorQN or Oral AS
64.7% 49.1% 82.0% 59.2% 31.9% 0.0%
WilcoxonRank SumTest p-value
0.0014 0.0004 <0.0001 <0.0001 0.2733 0.7853
58
Parasite Count with Rescued Parasite Count with Rescued Subjects Included (as LOCF)Subjects Included (as LOCF)
Median Fractional Remaining Parasite Count
Study 7 South AfricaN1=25, N2=4
Study 6 MalawiN1=75, N2=22
Study 5 ThailandN1=32, N2=10
12 hrs 24 hrs 12 hrs 24 hrs 12 hrs 24 hrs
RectalArtesunate
11.9% 0.6% 27.7% 0.2% 23.5% 0.0%
ComparatorQN or Oral AS
64.7% 49.1% 82.0% 59.2% 31.9% 0.0%
WilcoxonRank SumTest p-value
0.0014 0.0004 <0.0001 <0.0001 0.2733 0.2672
59
Recrudescence with Artesunate• Subjects malaria status assessed at
7, 14, and 28 days post-treatment.
• After positive result, subject was given additional malaria treatment.
• Obtaining complete follow-up was problematic.– Missing values considered successes.– Missing values considered failures.– Missing values ignored.
60
Cumulative Number of Recrudescences at Day 28
Study 5Thailand
Study 6Malawi
Study 7South Africa
Positive 0 39 (45%) 1Negative 27 19 23
Rectal AS
Missing 19 28 2Positive 0 5 (23%) 0Negative 9 7 7
ComparatorQN or Oral AS
Missing 8 10 1
61
Cumulative Recrudescence Rates Across Time in Study 6
Day 7 Day 14 Day 28Positive 14 (16%) 25 (29%) 39 (45%)Rectal
ArtesunateN=86
Missing 15 (17.4%) 20 (23.3%) 28 (32.6%)
Positive 0 (0.0%) 2 (9%) 5 (23%)ComparatorQN or Oral ASN=22 Missing 2 (9.1%) 5 (22.7%) 10 (45.5%)
Missing observations considered successes.
62
Cumulative Recrudescence Rates Across Time in Study 6
Day 7 Day 14 Day 28Positive 29 (34%) 45 (52%) 67 (78%)Rectal
ArtesunateN=86
Missing 15 (17.4%) 20 (23.3%) 28 (32.6%)
Positive 2 (9%) 7 (32%) 15 (68%)ComparatorQN or Oral ASN=22 Missing 2 (9.1%) 5 (22.7%) 10 (45.5%)
Missing observations considered failures.
63
Cumulative Recrudescence Rates Across Time in Study 6
Missing observations ignored.
Day 7 Day 14 Day 28Positive 14 (16%) 25 (29%) 39 (45%)Rectal
ArtesunateN=86
Missing 15 (17.4%) 20 (23.3%) 28 (32.6%)
Positive 0 (0.0%) 2 (9%) 5 (23%)ComparatorQN or Oral ASN=22 Missing 2 (9.1%) 5 (22.7%) 10 (45.5%)
64
Recrudescence with Artesunate
• Time-to-Recrudescence Analysis Artesunate group experienced recrudescence earlier and more often than the Quinine group (p=0.0130).
• Exploratory Covariate Analysis Relationships between time-to-recrudescence and variables other than treatment assignment were explored.
65
Summary
• Regardless of the method used to deal with rescued patients, 12 and 24 hour median fractional remaining parasite counts– were lower for Artesunate-treated subjects than
Quinine-treated subjects in studies 6 (Malawi) and 7 (South Africa).
– were not statistically significantly different for Oral and Rectal Artesunate in study 5 (Thailand).
66
Summary(cont’d)
• Recrudescence in Artesunate-treated subjects was earlier and more frequently than in Quinine-treated subjects.
• Exploratory Analysis did not reveal any other risk factors for recrudescense that might have impacted the treatment effect.
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