Is there a place for Corifollitropin alfa in
IVF/ICSI cycles? A systematic review
and meta-analysis
Mohamed Youssef, Madel...
Introduction
• Traditionally, gonadotrophins have to be
administered daily to maintain adequate
levels of FSH during COS, ...
Corifollitropin alfa
• Recently, a new hybrid molecule with sustained
follicle-stimulating activity, r FSH - Corifollitrop...
Corifollitropin alfa
• Corifollitropin alfa comprises :-
1.Alpha-subunit, which is identical to that of FSH,
2.Beta-subuni...
Corifollitropin alfa
• Single injection of Corifollitropin alfa can replace
the first 7 injections with standard daily
gon...
Aim of the review
• To evaluate the efficacy, safety and
tolerance of Corifollitropin alfa in comparison
with r FSH, in IV...
Inclusion criteria
• Type of studies: RCT
• Participants: Infertile couples undergoing IVF/ICSI
• Intervention: single inj...
Outcomes
• Primary outcome: Ongoing pregnancy rate
• Secondary outcomes:
1. Live birth rate, clinical pregnancy rate, misc...
Literature search
• Menstrual Disorders & Subfertility Group's Specialised Register of
controlled trials
• The Cochrane Ce...
Analysis plan – data extraction
• Data extraction by 2 reviewers (MY and MvW): studies
design, methodology and clinical ou...
Results
Flow diagram of study selection
kasr al ainy school of Medicine
Cairo University
Studies characteristicsStudies characteristics
• The overall methodological quality of the trials was good,
and they were ...
Studies characteristicsStudies characteristics
• Sample size calculations and intention to treat analyses
were performed i...
Pregnancy rates per randomised woman
Study or Subgroup
1.1.1 Live birth rate per woman randomized
Engage study 2009
Subtot...
No.oocytes and embryos
Study or Subgroup
2.1.1 No. oocytes retrieved per woman randomized
Corfillotropin alfa study
Devroe...
Adverse events
Study or Subgroup
3.1.1 OHSS incidence per woman randomized
Corfillotropin alfa study
Devroey 2004
Engage s...
Cause of cycle cancellation
Summary 1/2
The present meta-analysis indeed suggests
that corifollitropin alpha result in:-
1. Comparable pregnancy rates...
Summary 2/2
The main problem with Corifollitropin alfa:-
1. No dose adjustments can be made in patients
with a low respons...
Recommendations
• Alternative strategies to avoid cycle cancellations
may thus be explored further, for instance:-
• GnRH ...
Conclusion 2/2
• In view of its equivalence, corifollitropin alfa is
an alternative for daily rFSH injections in normal
re...
kasr al ainy school of Medicine
Cairo University
Thank youThank you
 Corifollitropin alfa (Elonva) : Meta-analysis
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Corifollitropin alfa (Elonva) : Meta-analysis

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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

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  • 29 landen, 785 klinieken, 367066 behandelingscycli waarvan 114672 IVF, Icsi
  • 29 landen, 785 klinieken, 367066 behandelingscycli waarvan 114672 IVF, Icsi
  • 29 landen, 785 klinieken, 367066 behandelingscycli waarvan 114672 IVF, Icsi
  • 29 landen, 785 klinieken, 367066 behandelingscycli waarvan 114672 IVF, Icsi
  • NVOG 0.1-2% van de behandelingen.
    Onstaat alleen in de luteale fase van de cyclus vooral na stimualtie me gonadodtroinen, met name in combinatie met een GnRH agonist.
    Het syndroom treedt vrijwel allen op as hcG wordt toegediend of door een zwangerschap wordt geproduceerd .
    ESHRE 9178 + 6119 = 15297 x 0,012=
  • Flow diagram for meta-analysis. Identification and selection of publications
  • which might be a potential source of bias that could have yielded exaggerated estimates of Corifollitropin alfa effect.
  • Heterogeneity may generate misleading results, but the results were consistent across the trials and there was no significant alteration in results in most outcomes between fixed and random model effects, used to evaluate the possible effect of heterogeneity
  • Forest plot of odds ratios of pooled trials comparing Corifollitropin alfa versus r FSH as regards number of oocytes and total number of embryos obtained per randomized women
  • Forest plot of odds ratios of pooled trials comparing Corifollitropin alfa versus r FSH as regards number of oocytes and total number of embryos obtained per randomized women
  • Forest plot of odds ratios of pooled trials comparing Corifollitropin alfa versus r FSH as regards number adverse events per randomized women
  • Forest plot of odds ratios of pooled trials comparing Corifollitropin alfa versus r FSH as regards the cause of cycle cancellation per randomized women
  • Corifollitropin alfa (Elonva) : Meta-analysis

    1. 1. 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
    2. 2. 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
    3. 3. 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
    4. 4. 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
    5. 5. 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
    6. 6. 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
    7. 7. 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
    8. 8. 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
    9. 9. 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
    10. 10. 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
    11. 11. Results
    12. 12. Flow diagram of study selection kasr al ainy school of Medicine Cairo University
    13. 13. 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),
    14. 14. 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)..
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. Cause of cycle cancellation
    19. 19. 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
    20. 20. 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
    21. 21. 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
    22. 22. 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
    23. 23. kasr al ainy school of Medicine Cairo University Thank youThank you

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