the efficacy of artesunate rectal suppositories leonard sacks medical officer cder. fda

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



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%



30

28-day recrudescences/new infections

0% 0%

45%

23%

4%0%

0%

10%

20%

30%

40%

50%



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


Rectal AS 20mg/kg After 12 hours IV AS 2.4mg/kg


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


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


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

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200000

250000

300000

0 12 24

Time (hours)

Pa

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Co

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Study 007: Parasite Count Across TimeQuinine Group

0

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100000

150000

200000

250000

300000

0 12 24

Time (hours)

Pa

ras

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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

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Study 006: Parasite Count Across TimeQuinine Group

0

100000

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Time (hours)

Pa

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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

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Study 005: Parasite Count Across TimeOral Artesunate Group

0

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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






RectalArtesunate

11.9% 0.6% 27.7% 0.1% 23.5% 0.0%


64.7% 49.1% 82.0% 59.2% 31.9% 0.0%


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)






RectalArtesunate

11.9% 0.6% 27.7% 0.2% 23.5% 0.0%


64.7% 49.1% 82.0% 59.2% 31.9% 0.0%


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


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



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


Missing observations ignored.


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.

the efficacy of artesunate rectal suppositories leonard sacks medical officer cder. fda

Documents

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