2014: Corifollitropin alfa (Elonva) : Meta-analysis
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Transcript of 2014: Corifollitropin alfa (Elonva) : Meta-analysis
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
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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
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Results
Flow diagram of study selection
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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),
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)..
Pregnancy rates per randomised womanStudy or Subgroup1.1.1 Live birth rate per woman randomizedEngage study 2009Subtotal (95% CI)Total eventsHeterogeneity: Not applicableTest for overall effect: Z = 1.37 (P = 0.17)
1.1.2 Ongoing pregnancy rate per woman randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: 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 randomizedCorfillotropin alfa studyEngage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: 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
3515
29468
412
3832278
438
Total
756756
24275
756268
1341
242756268
1266
Events
315
315
1110
28644
351
1430848
370
Total
750750
8324
750128985
83750128961
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 RatioM-H, Random, 95% CI
0.5 0.7 1 1.5 2r FSH Corifollitropin alfa
No.oocytes and embryosStudy or Subgroup2.1.1 No. oocytes retrieved per woman randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (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 randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (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 randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (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
9.3811.3613.713.3
7.899.5
10.810.7
6.757.468.37.1
SD
6.97.198.27.3
6.26.296.56.4
55.667504.2
Total
24275
756268
1341
24275
756286
1359
24275
756268
1341
Mean
7.77.9
12.510.6
5.98.69.27.8
5.15.37.46.1
SD
6.34.16.75.9
33
5.14.8
4.23.24.84.1
Total
8324
750128985
8324
750128985
8324
750128985
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 DifferenceIV, Random, 95% CI
-2 -1 0 1 2r FSH Corifillotropin alfa
Adverse events Study or Subgroup3.1.1 OHSS incidence per woman randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: 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 randomizedDevroey 2004Engage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: 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 randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: 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 randomizedCorfillotropin alfa studyEngage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: 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 randomizedCorfillotropin alfa studyDevroey 2004Engage study 2009Ensure study group 2010Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.00; Chi² = 1.16, df = 3 (P = 0.76); I² = 0%Test for overall effect: Z = 2.42 (P = 0.02)
Events
44
1418
40
213720
78
83
8319
113
32710
40
53116222
148
Total
24275
756268
1341
75756268
1099
24275
756268
1341
242756268
1266
24275
756268
1341
Events
2296
19
4378
49
11
6610
78
3214
28
151
418
65
Total
8324
750128985
24750128902
8324
750128985
83750128961
8324
750128985
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 RatioM-H, Random, 95% CI
0.01 0.1 1 10 100r FSH Corifollitropin alfa
Cause of cycle cancellation
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
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 MedicineCairo University
kasr al ainy school of MedicineCairo University
Thank youThank you