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					The efficacy of Artesunate rectal
          suppositories
          Leonard Sacks
          Medical Officer
           CDER. FDA
             FDA Review Team for
                NDA 21-242
• Regulatory Project Manager:        M. Bacho, B.S.
• Chemistry Reviewer:                J. Smith, Ph.D.; D. Cummings
• Microbiology Reviewer:             K. Suvarna, Ph.D.
• Biopharmacology/Biopharmaceutics
  Reviewer                           J. Meyer, Pharm. D.
• Pharmacotoxicologist Reviewer:     S. Kunder, Ph.D.
• Statistical Reviewer:              R. Davi, M.S.
• Medical Reviewers:                 L. Sacks, MB.B.Ch.
                                     R. Johann-Liang, M.D.



                                                                    2
Background




             3
        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




                                                 4
           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




                                                     5
                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

                                                 6
      Rectal artesunate- a suitable
               candidate?
• Artemisinin               • Short half life
  derivatives are potent    • Associated with
  antimalarials               recrudescence
• Used successfully in      • Potential neurotoxicity
  areas of drug-sensitive
  and resistant P
  falciparum



                                                    7
            Clinical pharmacology
  Adult healthy subjects, 400-mg single dose
                                        Cmax
  Analyte         Tmax (hours)                             T1/2
                                      (ng/mL)
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


                                                                     8
         Clinical pharmacology

• In the course of product development, the
  formulation used in clinical trials and the
  formulation to be marketed were different.




                                                9
   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                                      10
   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
                                                        11
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?




                                              12
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.
                                                                         13
  Other problems in modeling the
           projected use
        Clinical studies                   Projected use
• Most lived in malaria areas -   • May be used in US travelers
  some immunity                     and residents of malaria areas
• Diagnosis was confirmed on      • Diagnosis will not be confirmed
  smear                             before treatment

• Moderately severe (entry        • All degrees of severity
  parasitemia…)
• Patients were hospitalized      • Not hospitalized




                                                                 14
    Other problems in modeling the
        projected use (cont’d)
           Clinical studies                      Projected use
•   Ancillary treatment provided        • No ancillary treatment
    (fluids, glucose anticonvulsants,     available in the field
    antipyretics etc)
•   Suppository retention was           • Retention may be supervised
    supervised
•   Patients failing on                 • No rescue in the field
    parasitological grounds were
    rescued
•   Definitive therapy provided at      • Access to definitive treatment
    24 hours                              depends on local infrastructure



                                                                        15
        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

                                                   16
Studies of efficacy

    NDA 21-242




                      17
   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




                                                    18
   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


                                                  19
       Drug regimens in pivotal studies
                         Thailand (005)                Malawi (006)                South Africa (007)
Experimental       Rectal AS (10mg/kg)        Rectal AS (10mg/kg) single        Rectal AS (10mg/kg)
arm                single dose                dose                              single dose
Comparator         Oral AS (4 mg/kg) single   Quinine 10mg/kg IM or IV          Quinine 10mg/kg IM or
                   dose                       at 0, 4 hrs then 12 hourly till   IV at 0, 4 and 12hrs
                                              oral treatment tolerated
Consolidation      24 hrs:                    24 hrs:                           24 hrs:
regimen            Oral AS (2mg/kg)           Oral SP (25mg/kg SDX)             Oral SP (3 tablets)
                   48 hrs:                    (or “standard dose”               single dose
                   Oral AS (2mg/kg)           parenteral quinine if unable      (or IM quinine 10mg/kg
                   + MQ (15mg/kg)             to take orally)                   if unable to take orally)
                   72 hrs:
                   Oral AS (1mg/kg)           SP given at 24 hours in
                   + MQ (10mg/kg)             experimental arm
                   Daily for 6 more days:     SP given after a minimum of
                   Oral AS (1mg/kg)           2 doses of quinine in
                                              comparator arm

 AS = artesunate
 SP = sulfadoxine/pyrimethamine
 MQ = mefloquine
                                                                                                            20
     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



                                                  21
     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




                                             22
    Inclusion and exclusion criteria
                                            Location (Study No.)
                     Thailand (005)              Malawi (006)            South Africa (007)
Age              6 months-15 years          1 – 10 years               16 years – 65 years
Eligible         >4% (200,000/ l)          >0.4% (<20,000/l)         -
parasitemia
(P falciparum)
Clinical         -                          Unable to eat or drink     Unable to eat or drink
eligibility                                 or
                                            Impaired consciousness
Exclusion        Diarrhea                   Diarrhea                   Diarrhea
                 Unable to eat or drink     -                          -
                 Previous antimalarial in   Previous antimalarial in   Previous antimalarial in
                 past 24 hrs                past 24 hours              past 24 hours
                 Severe malaria:            Severe malaria:            Severe malaria:
                  Acidotic                  Deep breathing            Respiratory distress
                  Hct < 15%                 Hct < 18%
                  Jaundice                  Jaundice                  Jaundice
                  Bleeding                  Bleeding                  Bleeding
                  Shock                     Shock                     Shock
                  Decreased                 Stupor or coma            Coma
                     consciousness           Convulsions               >1 Convulsion
                                                                        Renal failure
                                                                        Hypoglycemia
                                                                        Lactate < 5 mmol/l
                 Parasitemia >20%           Parasitemia >10%           Parasitemia >10%
                                                                                           23
            Baseline characteristics
                                      Location (Study No.)
                     Thailand (005)      Malawi (006)      South Africa (007)
Number of patients
    Artesunate            46                  87                   27
    Comparator            17                  22                    8
Mean Age
    Artesunate          7 years            4 ½ years             29 yrs
    Comparator          7 years             4 years              25 yrs
% Males                 63.5%                61.5%                51%

Entry parasitemia       Median             Median               Median
      Artesunate        245,366            183,390              51,240
      Comparator        376,649            230,739              58,340
Platelet count          Median            Geom mean             Median
      Artesunate         85,000             74,500              80,000
      Comparator        129,000             67,000              38,500




                                                                                24
         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   Rescue in both arms
                      artesunate arm


                                                                    25
     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 evaluation
24-hour parasitological    All 24-hour clinical successes whose 24 hour parasite
success                    count was  of the baseline count
                                        10%

28-day recrudescence/      Any patient who received study drug and was found to
re-infection               have a recurrence of parasitemia between the time that
                           therapy was stopped and day 28.

WHO primary endpoint was fractional remaining parasite count at 24 hours


                                                                                    26
    Study-related events with an
     impact on clinical results
                                                   Location (Study No.)
                             Thailand (005)           Malawi (006)              South Africa
                                                                                   (007)
Number of patients
      Artesunate                   46                        87                     27
      Comparator                   17                        22                     8
Exclusions
      Artesunate                    5                         3                      1
      Comparator                    3                         0                      1
Rescued for 12 hour
parasitemia  of baseline
              60%
      Artesunate                    7                         3                      1
      Comparator                    4            0 ( no provision for rescue)        2
Clinical deterioration
      Artesunate                    1                         4                      0
      Comparator                    0                         0                      0
Death
      Artesunate                    1                         0                      0
      Comparator                    0                         0                      0
Other failures
      Artesunate            1 (expelled supps)               1                       0
      Comparator                   N/A                      N/A                      0
                                                                                               27
        24-hour clinical success
100%                      100%     96%
                    91%
 90%    76%                              75%
 80%          71%
 70%
 60%
 50%                                            Artesunate
 40%                                            Comparator
 30%
 20%
 10%
  0%
       Thailand     Malawi       South Africa
                                                     28
   24-hour parasitological success
100%
                   88%           85%
 90%
       76%
 80%         71%
 70%
 60%
 50%                                          Artesunate
 40%                                          Comparator
 30%                                   25%
 20%                     14%
 10%
  0%
       Thailand    Malawi      South Africa
                                                   29
      28-day recrudescences/new
              infections
50%              45%

40%

30%
                       23%
                                            Artesunate
20%                                         Comparator


10%
                               4%
       0% 0%                        0%
0%
      Thailand   Malawi      South Africa       30
     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.


                                                              31
     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.


                                               32
 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)




                                           33
Treatment regimen (Study 014)

 First 24 hours   Rectal artesunate 400mg (single
                  dose)
 Follow-up        Oral artesunate 200mg daily X 3
                  Mefloquine 750mg daily X 2




                                                    34
            Study population
•   Thailand
•   Hospitalized, adult patients
•   Uncomplicated “moderately severe” malaria
•   23 patients per arm




                                            35
   Median parasite counts/μl
   following treatment with 3
formulations of rectal artesunate
46720
           40680



        30690



                                                             2 x 200mg
                                                             4 x 100mg
                             13080                           1 x 400mg
                      9980

                   3890

                                     30 86 62    1   0   0

  baseline         12 hours          24 hours   48 hours         36
Recrudescences/new infections?




                             37
  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.
                                                       38
         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)



                                            39
                 Studies 003 and 004
                                          Location (Study No.)
                               Thailand (003)               Ghana (004)
IV AS 2.4mg/kg            12 patients (Group 1)      0 patients
After 12 hrs, Rectal AS
10mg/kg
Rectal AS 10mg/kg         12 patients (Group 2)     12 patients (Group 1)
After 12 hours IV AS
2.4mg/kg
IV AS 2.4mg/kg            12 patients (Group 3)     12 patients (Group 3)
After 12 hrs, Rectal AS
20mg/kg
Rectal AS 20mg/kg         12 patients (Group 4)     12 patients (Group 2)
After 12 hours IV AS
2.4mg/kg



                                                                            40
                 “Consolidation therapy”

                                        Location (Study No.)
                          Thailand (003)                     Ghana (004)
“consolidation     Mefloquine at 36 and 48 hours Chloroquine over 3 days
therapy”                                           (sulfadoxine-pyrimethamine if
                                                   intolerant of chloroquine)




                                                                            41
               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 Cerebral malaria (coma  2 on
(e.g. pulmonary edema, renal failure,       Blantyre scale) hypoglycemia, blood
shock)                                      lactate  5 mmol/l or Hct < 15%
Rectal abnormalities/acute diarrhea         Rectal abnormalities/acute diarrhea
                                            Previous antimalarial treatment


                                                                                  42
           24-hour clinical success rate
                    Regimen             Short term clinical success
             IV AS 2.4 mg/kg,                       12/12
             Rectal AS 10 mg/kg
             Rectal AS 10 mg/kg,                    23/24
             IV AS 2.4 mg/kg
             IV AS 2.4 mg/kg,                       22/23
             Rectal AS 20 mg/kg
             Rectal AS 20 mg/kg,                   22/24 *
             IV AS 2.4 mg/kg
*In this treatment group, 2 patients progressed clinically to severe malaria




                                                                         43
          >90% clearance of baseline
         parasitemia at 12 and 24 hours
         Regimen                      12 hours                    24 hours
IV AS 2.4 mg/kg,                        1/12                        8/12
Rectal AS 10 mg/kg
Rectal AS 10 mg/kg,                     5/23                        21/23
IV AS 2.4 mg/kg
IV AS 2.4 mg/kg                         5/23                        20/22
Rectal AS 20 mg/kg
Rectal AS 20 mg/kg                      3/24                       21/23 *
IV AS 2.4 mg/kg
*In this treatment group, 2 patients progressed clinically to severe malaria



                                                                               44
       Recurrent parasitemia during
         2-3 weeks after therapy

                            Recrudescence rate among patients
                                 allocated to treatment
Mefloquine                              7/48 15%
Chloroquine                             7/23 30%
Sulfadoxine-pyrimethamine               2/9 22%




                                                          45
      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


                                           46
                 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)                               47
              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?                                     48
            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.

                                                  49
NDA 21-242 Rectal Artesunate

       Ruthanna Davi, M.S.
     Statistical Reviewer, FDA


                                 50
NDA 21-242 – Rectal Artesunate

 • Interpretation of Parasite Count Analyses in
   light of Rescued Patients
 • Recrudescence with Artesunate
 • Other risk factors for Recrudescence




                                              51
         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.
                                               52
                          Study 007: Parasite Count Across Time
                                 Rectal Artesunate Group
                                                                       Excluding Rescued
                 300000

                 250000
                                                                       Artesunate Subject, M34
Parasite Count




                 200000
                                                                       Including Rescued
                 150000

                 100000
                                                                       Artesunate Subject, M34
                  50000                                                Including (as LOCF) Rescued
                      0
                               0                12                24
                                                                       Artesunate Subject, M34
                                            Time (hours)



                          Study 007: Parasite Count Across Time
                                     Quinine Group

                 300000
                                                                       Excluding Rescued Quinine
                 250000
                                                                       Subjects, M02 & M27
Parasite Count




                 200000
                                                                       Including Rescued Quinine
                 150000

                 100000
                                                                       Subjects, M02 & M27
                  50000
                                                                       Including (as LOCF) Rescued
                      0
                              0                 12                24
                                                                       Quinine Subjects, M02 & M27
                                                                                             53
                                            Time (hours)
                          Study 006: Parasite Count Across Time
                                 Rectal Artesuante Group
                                                                       Excluding Rescued
                                                                       Artesunate Subject, 6, 44,
                 700000
                 600000
                                                                       57, 60, 70, 101, 104, &105
Parasite Count




                 500000
                 400000
                                                                       Including Rescued
                 300000                                                Artesunate Subjects; 6, 44,
                 200000
                 100000
                                                                       57, 60, 70, 101, 104, & 105
                      0
                              0        6         12        18     24   Including (as LOCF) Rescued
                                            Time (hours)
                                                                       Artesunate Subjects, 6, 44,
                          Study 006: Parasite Count Across Time        57, 60, 70, 101, 104, & 105
                                      Quinine Group
                                                                       Protocol did not require
                 700000
                 600000
                                                                       Rescue of Quinine
Parasite Count




                 500000                                                Subjects
                 400000
                 300000
                 200000
                 100000
                      0
                             0         6        12         18     24
                                            Time (hours)                                     54
                          Study 005: Parasite Count Across Time
                                 Rectal Artesunate Group
                                                                       Excluding Rescued Rectal
                 900000
                                                                       Artesunate Subjects, 2, 8, 14,
                 800000
                 700000
                                                                       16, 18, 23, 36, & 41
Parasite Count




                 600000
                 500000
                                                                       Including Rescued Rectal
                 400000
                 300000
                                                                       Artesunate Subjects, 2, 8, 14,
                 200000
                 100000
                                                                       16, 18, 23, 36, & 41
                      0                                                Including (as LOCF) Rescued
                                 0              12                24
                                            Time (hours)               Rectal Artesunate Subject, 2,
                                                                       8, 14, 16, 18, 23, 36, & 41
                          Study 005: Parasite Count Across Time
                                  Oral Artesunate Group                Excluding Rescued Oral
                 900000                                                Artesunate Subjects, 12, 32,
                 800000
                 700000                                                38, & 61
Parasite Count




                 600000
                 500000                                                Including Rescued Oral
                 400000
                 300000                                                Artesunate Subjects, 12, 32,
                 200000
                 100000                                                38, & 61
                      0                                                Including (as LOCF) Rescued
                                 0              12                24
                                            Time (hours)               Oral Artesunate Subjects, 12,
                                                                                              55
                                                                       32, 38, & 61
        Parasite Count with Rescued
             Subjects Excluded
            Median Fractional Remaining Parasite Count
                Study 7 South Africa   Study 6 Malawi    Study 5 Thailand
                   N1=25, N2=4          N1=75, N2=22       N1=32, N2=10
                 12 hrs    24 hrs      12 hrs   24 hrs   12 hrs   24 hrs
Rectal           11.1%      0.6%       27.6%    0.1%     19.4%     0.0%
Artesunate
Comparator       51.2%     27.8%       82.0%    59.2%    21.9%     0.0%
QN or Oral AS
Wilcoxon
Rank Sum        0.0047     0.0011 <0.0001 <0.0001 0.3083          0.3164
Test p-value

                                                                    56
       Parasite Count with Rescued
            Subjects Included
                 Median Fractional Remaining Parasite Count

                Study 7 South Africa     Study 6 Malawi    Study 5 Thailand
                    N1=26, N2=6           N1=83, N2=22       N1=40, N2=14
                 12 hrs    24 hrs       12 hrs    24 hrs   12 hrs    24 hrs

Rectal          11.9%      0.6%        27.7%      0.1%     23.5%    0.0%
Artesunate
Comparator      64.7%      49.1%       82.0%     59.2%     31.9%    0.0%
QN or Oral AS
Wilcoxon
Rank Sum     0.0014       0.0004       <0.0001 <0.0001 0.2733       0.7853
Test p-value

                                                                      57
       Parasite Count with Rescued
       Subjects Included (as LOCF)
                 Median Fractional Remaining Parasite Count

                Study 7 South Africa     Study 6 Malawi    Study 5 Thailand
                   N1=25, N2=4            N1=75, N2=22       N1=32, N2=10
                 12 hrs     24 hrs      12 hrs    24 hrs   12 hrs    24 hrs

Rectal          11.9%       0.6%       27.7%      0.2%     23.5%     0.0%
Artesunate
Comparator      64.7%      49.1%       82.0%     59.2%     31.9%     0.0%
QN or Oral AS
Wilcoxon
Rank Sum        0.0014     0.0004      <0.0001 <0.0001 0.2733       0.2672
Test p-value

                                                                      58
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.
                                             59
        Cumulative Number of
       Recrudescences at Day 28
                            Study 5    Study 6     Study 7
                           Thailand    Malawi    South Africa
Rectal AS       Positive     0        39 (45%)       1
                Negative     27           19         23
                Missing      19           28         2
Comparator      Positive     0         5 (23%)       0
QN or Oral AS
                Negative     9             7         7
                Missing      8            10         1
                                                          60
Cumulative Recrudescence Rates
   Across Time in Study 6
                          Day 7         Day 14        Day 28
Rectal     Positive       14 (16%)      25 (29%)      39 (45%)
Artesunate Missing         15 (17.4%)    20 (23.3%)    28 (32.6%)
N=86
Comparator Positive       0 (0.0%)       2 (9%)        5 (23%)
QN or Oral AS
N=22            Missing     2 (9.1%)     5 (22.7%)     10 (45.5%)

  Missing observations considered successes.

                                                           61
Cumulative Recrudescence Rates
   Across Time in Study 6
                          Day 7       Day 14        Day 28
Rectal     Positive 29 (34%)          45 (52%)      67 (78%)
Artesunate Missing 15 (17.4%)          20 (23.3%)    28 (32.6%)
N=86
Comparator Positive 2 (9%)             7 (32%)      15 (68%)
QN or Oral AS
N=22            Missing    2 (9.1%)    5 (22.7%)     10 (45.5%)


     Missing observations considered failures.

                                                          62
 Cumulative Recrudescence Rates
    Across Time in Study 6
                          Day 7         Day 14        Day 28
Rectal     Positive       14 (16%)      25 (29%)      39 (45%)
Artesunate Missing         15 (17.4%)    20 (23.3%)    28 (32.6%)
N=86
Comparator Positive       0 (0.0%)       2 (9%)        5 (23%)
QN or Oral AS
N=22            Missing     2 (9.1%)     5 (22.7%)     10 (45.5%)


                Missing observations ignored.

                                                              63
 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.
                                              64
                    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).


                                                       65
                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.


                                              66

				
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