Elonva is a new drug for ovarian stimulation in IVF that has to be studied through randomised controlled trials. Moreover, Meta-analysis of RCTs would enable clinicians and researchers to identify potential benefits and risks

2. Is there a place for Corifollitropin alfa in
IVF/ICSI cycles? A systematic review
and meta-analysis
Mohamed Youssef, Madelon van Wely M; Khattab S,
Aboulfoutouh I, van der Veen F, Hesham Al-Inany
Cairo University

3. Introduction
• Traditionally, gonadotrophins have to be
administered daily to maintain adequate
levels of FSH during COS, because:-
1.Short elimination half-life
2.Rapid metabolic clearance
kasr al ainy school of Medicine
Cairo University

4. Corifollitropin alfa
• Recently, a new hybrid molecule with sustained
follicle-stimulating activity, r FSH - Corifollitropin
alfa- has become available, it has :-
1.A longer half life
2.Interacts only with FSH-receptors without LH
activity
kasr al ainy school of Medicine
Cairo University

5. Corifollitropin alfa
• Corifollitropin alfa comprises :-
1.Alpha-subunit, which is identical to that of FSH,
2.Beta-subunit, which is produced by the fusion of
the C-terminal peptide from the beta-subunit of
chorionic gonadotropin to the beta-subunit of
FSH
kasr al ainy school of Medicine
Cairo University

6. Corifollitropin alfa
• Single injection of Corifollitropin alfa can replace
the first 7 injections with standard daily
gonadotropins.
• This makes corifollitropin alpha potentially more
patient friendly and may lead to a lower dropout
rate of patients,
if safety and effectiveness have first been
demonstrated!!!
kasr al ainy school of Medicine
Cairo University

7. Aim of the review
• To evaluate the efficacy, safety and
tolerance of Corifollitropin alfa in comparison
with r FSH, in IVF or ICSI cycles.
kasr al ainy school of Medicine
Cairo University

8. Inclusion criteria
• Type of studies: RCT
• Participants: Infertile couples undergoing IVF/ICSI
• Intervention: single injection of Corifollitropin alfa
versus daily r FSH administration
kasr al ainy school of Medicine
Cairo University

9. Outcomes
• Primary outcome: Ongoing pregnancy rate
• Secondary outcomes:
1. Live birth rate, clinical pregnancy rate, miscarriage rate,
2. Duration of stimulation & amount of FSH,
3. Number of retrieved oocytes, number of mature oocytes,
number of embryos obtained,
4. OHSS incidence, and adverse events .i.e. Local and
systemic reactions
kasr al ainy school of Medicine
Cairo University

10. Literature search
• Menstrual Disorders & Subfertility Group's Specialised Register of
controlled trials
• The Cochrane Central Register of Controlled Trials (CENTRAL)
• MEDLINE (1966 to Jan 2011)
• EMBASE (1980 to Jan 2011)
• National Research Register
• Web-based trials databases such as Current Controlled Trials
• References check.
• We also contacted drug companies for any published, unpublished or
ongoing studies not identified with our search strategy
• No language restriction
kasr al ainy school of Medicine
Cairo University

11. Analysis plan – data extraction
• Data extraction by 2 reviewers (MY and MvW): studies
design, methodology and clinical outcomes
• Risk for bias:
– 1. Sequence generation.
– 2. Allocation concealment.
– 3. Blinding?
– 4. Other forms of bias
• Missing details - authors/sponsor contacted
kasr al ainy school of Medicine
Cairo University

12. Results

13. Flow diagram of study selection
kasr al ainy school of Medicine
Cairo University

14. Studies characteristicsStudies characteristics
• The overall methodological quality of the trials was good,
and they were published as a full manuscript in peer-
reviewed journals.
• The method of allocation by using computer generated
randomization or sealed envelopes were reported in all
studies.
• Two studies were double-blind, double-dummy and the
other two were open labelled studies (Corifollitropin alfa
study group 2008 and Devroey et al., 2004),

15. Studies characteristicsStudies characteristics
• Sample size calculations and intention to treat analyses
were performed in all studies.
• One study was conducted in a single centre and three
were multicenter studies.
• There was clinical heterogeneity between trials in the
type of patients (> 60 kg or ≤ 60 kg) and dose of
Corifollitropin alfa; (60 µg, 100 µg, 120 µg, 150 µg, 180
µg or 240 µg)..

16. Pregnancy rates per randomised woman
Study or Subgroup
1.1.1 Live birth rate per woman randomized
Engage study 2009
Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.37 (P = 0.17)
1.1.2 Ongoing pregnancy rate per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.09; Chi² = 7.32, df = 3 (P = 0.06); I² = 59%
Test for overall effect: Z = 1.08 (P = 0.28)
1.1.3 Clinical pregnancy rate per woman randomized
Corfillotropin alfa study
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.03; Chi² = 3.18, df = 2 (P = 0.20); I² = 37%
Test for overall effect: Z = 0.55 (P = 0.58)
Events
344
344
35
15
294
68
412
38
322
78
438
Total
756
756
242
75
756
268
1341
242
756
268
1266
Events
315
315
11
10
286
44
351
14
308
48
370
Total
750
750
83
24
750
128
985
83
750
128
961
Weight
100.0%
100.0%
18.2%
12.0%
41.1%
28.8%
100.0%
14.8%
57.7%
27.4%
100.0%
M-H, Random, 95% CI
1.15 [0.94, 1.41]
1.15 [0.94, 1.41]
1.11 [0.53, 2.29]
0.35 [0.13, 0.94]
1.03 [0.84, 1.27]
0.65 [0.41, 1.03]
0.80 [0.54, 1.20]
0.92 [0.47, 1.80]
1.06 [0.87, 1.31]
0.68 [0.44, 1.07]
0.92 [0.69, 1.23]
Corifollitropin alfa r FSH Odds Ratio Odds Ratio
M-H, Random, 95% CI
0.5 0.7 1 1.5 2
r FSH Corifollitropin alfa

17. No.oocytes and embryos
Study or Subgroup
2.1.1 No. oocytes retrieved per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Heterogeneity: Tau² = 0.48; Chi² = 6.03, df = 3 (P = 0.11); I² = 50%
Test for overall effect: Z = 4.00 (P < 0.0001)
2.1.2 No. MII oocytes per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Heterogeneity: Tau² = 0.19; Chi² = 5.17, df = 3 (P = 0.16); I² = 42%
Test for overall effect: Z = 5.61 (P < 0.00001)
2.1.3 No. of embryos obtained per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Heterogeneity: Tau² = 0.00; Chi² = 1.67, df = 3 (P = 0.64); I² = 0%
Test for overall effect: Z = 4.18 (P < 0.0001)
Mean
9.38
11.36
13.7
13.3
7.89
9.5
10.8
10.7
6.75
7.46
8.3
7.1
SD
6.9
7.19
8.2
7.3
6.2
6.29
6.5
6.4
5
5.66
750
4.2
Total
242
75
756
268
1341
242
75
756
286
1359
242
75
756
268
1341
Mean
7.7
7.9
12.5
10.6
5.9
8.6
9.2
7.8
5.1
5.3
7.4
6.1
SD
6.3
4.1
6.7
5.9
3
3
5.1
4.8
4.2
3.2
4.8
4.1
Total
83
24
750
128
985
83
24
750
128
985
83
24
750
128
985
Weight
21.4%
13.2%
39.3%
26.0%
100.0%
25.4%
10.7%
41.2%
22.7%
100.0%
33.6%
12.4%
0.0%
53.9%
100.0%
IV, Random, 95% CI
1.68 [0.07, 3.29]
3.46 [1.15, 5.77]
1.20 [0.44, 1.96]
2.70 [1.36, 4.04]
1.99 [1.02, 2.97]
1.99 [0.98, 3.00]
0.90 [-0.96, 2.76]
1.60 [1.01, 2.19]
2.90 [1.79, 4.01]
1.92 [1.25, 2.59]
1.65 [0.55, 2.75]
2.16 [0.35, 3.97]
0.90 [-52.56, 54.36]
1.00 [0.13, 1.87]
1.36 [0.72, 2.00]
Corifillotropin alfa r FSH Mean Difference Mean Difference
IV, Random, 95% CI
-2 -1 0 1 2
r FSH Corifillotropin alfa

18. Adverse events
Study or Subgroup
3.1.1 OHSS incidence per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 1.45, df = 3 (P = 0.69); I² = 0%
Test for overall effect: Z = 0.83 (P = 0.40)
3.1.2 Adverse events per woman randomized
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 1.12, df = 2 (P = 0.57); I² = 0%
Test for overall effect: Z = 0.53 (P = 0.60)
3.1.3 Multiple pregnancy per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 1.28, df = 3 (P = 0.73); I² = 0%
Test for overall effect: Z = 1.31 (P = 0.19)
3.1.4 Early miscarriage per woman randomized
Corfillotropin alfa study
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.05; Chi² = 2.37, df = 2 (P = 0.31); I² = 16%
Test for overall effect: Z = 0.22 (P = 0.83)
3.1.5 Cancellation rate per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage study 2009
Ensure study group 2010
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 1.16, df = 3 (P = 0.76); I² = 0%
Test for overall effect: Z = 2.42 (P = 0.02)
Events
4
4
14
18
40
21
37
20
78
8
3
83
19
113
3
27
10
40
53
11
62
22
148
Total
242
75
756
268
1341
75
756
268
1099
242
75
756
268
1341
242
756
268
1266
242
75
756
268
1341
Events
2
2
9
6
19
4
37
8
49
1
1
66
10
78
3
21
4
28
15
1
41
8
65
Total
83
24
750
128
985
24
750
128
902
83
24
750
128
985
83
750
128
961
83
24
750
128
985
Weight
10.7%
10.1%
44.2%
35.0%
100.0%
10.6%
68.6%
20.8%
100.0%
2.1%
1.8%
81.3%
14.8%
100.0%
12.6%
65.2%
22.3%
100.0%
24.4%
2.2%
59.3%
14.1%
100.0%
M-H, Random, 95% CI
0.68 [0.12, 3.79]
0.62 [0.11, 3.61]
1.55 [0.67, 3.61]
1.46 [0.57, 3.78]
1.27 [0.72, 2.22]
1.94 [0.59, 6.37]
0.99 [0.62, 1.58]
1.21 [0.52, 2.83]
1.11 [0.75, 1.63]
2.80 [0.35, 22.76]
0.96 [0.09, 9.67]
1.28 [0.91, 1.80]
0.90 [0.41, 2.00]
1.23 [0.90, 1.67]
0.33 [0.07, 1.69]
1.29 [0.72, 2.30]
1.20 [0.37, 3.91]
1.07 [0.59, 1.94]
1.27 [0.67, 2.40]
3.95 [0.48, 32.34]
1.54 [1.03, 2.32]
1.34 [0.58, 3.10]
1.47 [1.08, 2.02]
Corifollitropin alfa r FSH Odds Ratio Odds Ratio
M-H, Random, 95% CI
0.01 0.1 1 10 100
r FSH Corifollitropin alfa

19. Cause of cycle cancellation

20. Summary 1/2
The present meta-analysis indeed suggests
that corifollitropin alpha result in:-
1. Comparable pregnancy rates
2. Cancellation of cycles due to high
ovarian response and high risk to
develop OHSS
kasr al ainy school of Medicine
Cairo University

21. Summary 2/2
The main problem with Corifollitropin alfa:-
1. No dose adjustments can be made in patients
with a low response or in patients with a risk of
high response
2. Studies evaluating patients’ preference,
comfort and compliance of corifollitropin alpha
as compared to standard daily FSH are lacking.
kasr al ainy school of Medicine
Cairo University

22. Recommendations
• Alternative strategies to avoid cycle cancellations
may thus be explored further, for instance:-
• GnRH agonist could be used to replace HCG for final oocyte
maturation triggering after patients’ councelling.
• Mid to late follicular phase initiation of low-dose exogenous long
acting corifollitropin alfa plus GnRH antagonist as a mild stimulation
strategy might induce dominant follicle development without
increasing the risk of OHSS and cycle cancellation.
kasr al ainy school of Medicine
Cairo University

23. Conclusion 2/2
• In view of its equivalence, corifollitropin alfa is
an alternative for daily rFSH injections in normal
responder patients undergoing ovarian
stimulation with GnRH antagonist cycles with
comparable pregnancy rates
kasr al ainy school of Medicine
Cairo University

24. kasr al ainy school of Medicine
Cairo University
Thank youThank you