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

kasr al ainy school of MedicineCairo University

Results

Flow diagram of study selection

kasr al ainy school of MedicineCairo University

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