efficacy and safety of pergoveris® in assisted reproductive ......ivf/icsi treatment running title:...

For peer review only

Efficacy and Safety of Pergoveris® in Assisted Reproductive Technology – ESPART: rationale and design of a randomised

controlled trial in poor ovarian responders undergoing IVF/ICSI treatment

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008297

Article Type: Protocol

Date Submitted by the Author: 24-Mar-2015

Complete List of Authors: Humaidan, Peter; The Fertility Clinic, Skive Regional Hospital Schertz, Joan; EMD Serono Research & Development Institute, Fertility Global Clinical Development Unit Fischer, Robert; MVZ Fertility Center Hamburg GmbH,

<b>Primary Subject Heading</b>:

Reproductive medicine

Secondary Subject Heading: Reproductive medicine

Keywords: REPRODUCTIVE MEDICINE, Subfertility < GYNAECOLOGY, Clinical trials < THERAPEUTICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Efficacy and Safety of Pergoveris® in

Assisted Reproductive Technology – ESPART: rationale and design of a randomised controlled trial in poor ovarian responders undergoing IVF/ICSI treatment

Running title: RCT of r-hFSH with/without r-hLH in POR patients

P. Humaidan,1* J. Schertz,

2 R. Fischer

3

1The Fertility Clinic, Skive Regional Hospital, Faculty of Health, Aarhus University,

7800 Skive, Denmark; 2Fertility Global Clinical Development Unit, EMD Serono

Research & Development Institute, Inc., Billerica, MA 01821, USA; 3Fertility Center

Hamburg, 20095 Hamburg, Germany

*Corresponding author:

Peter Humaidan, Professor, DMSc, The Fertility Clinic, Skive Regional Hospital,

Faculty of Health, Aarhus University, Resenvej 25, 7800 Skive, Denmark

Tel.: + 45 23 81 59 91; E-mail: [email protected]

Keywords: assisted reproductive technologies – Bologna criteria – poor ovarian

response – recombinant human follicle-stimulating hormone – recombinant human

luteinizing hormone

Word count (excluding title page, abstract and references): 3289

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ABSTRACT

Introduction: The results of a recent meta-analysis showed that adding recombinant

human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating

hormone (r-hFSH) for ovarian stimulation was beneficial in poor responders, resulting

in a 30% relative increase in the clinical pregnancy rate compared with r-hFSH

monotherapy. However, a limitation of the meta-analysis was that the included studies

used heterogeneous definitions of poor ovarian response (POR). Furthermore, the use

of r-hLH supplementation during ovarian stimulation is a topic of ongoing debate and

well-designed, adequately powered, multicentre, randomised controlled trials in this

setting are warranted. Therefore, the objective of the ESPART trial is to explore the

possible superiority of a fixed-dose combination of r-hFSH plus r-hLH over r-hFSH

monotherapy in patients with POR, as per a definition aligned with the European

Society of Human Reproduction and Embryology (ESHRE) Bologna criteria.

Methods and analysis: Phase III, randomised, single-blind, parallel-group trial in

women undergoing in vitro fertilization and/or intracytoplasmic sperm injection.

Approximately 946 women aged 18– <41 years from 18 countries will be randomised

(1:1) to receive a fixed-dose combination of r-hFSH plus r-hLH in a 2:1 ratio

(Pergoveris®

) or r-hFSH monotherapy (GONAL-f®

). The primary endpoint is the total

number of retrieved oocytes per subject. Secondary endpoints include: ongoing

pregnancy rate, live birth rate, implantation rate, biochemical pregnancy rate and

clinical pregnancy rate. Safety endpoints include: incidence and severity of ovarian

hyperstimulation syndrome and of adverse events and serious adverse events.

Ethics and dissemination: The study will be performed in accordance with the

ethical principles that have their origin in the Declaration of Helsinki, with the

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International Conference on Harmonisation–Good Clinical Practice guidelines and all

applicable regulatory requirements. All participants will provide written informed

consent prior to entry. The results of this study will be publically disseminated.

Trial registration numbers: ClinicalTrials.gov identifier: NCT02047227; EudraCT

Number: 2013-003817-16.

Strengths and limitations of this study:

• To the authors’ knowledge, the ESPART study will be the largest randomised

controlled trial (RCT) conducted in women with poor ovarian response (POR).

Furthermore, it is the first Phase III study with a superiority design that will

evaluate the possible advantage of the addition of r-hLH to r-hFSH for

controlled ovarian stimulation in this patient population. The ESPART study

fulfills the criteria of a robust, well-designed RCT, which uses a definition of

POR that is consistent with the Bologna criteria.

• Although the ESPART study will recruit women with POR, as aligned with

the Bologna criteria, clinical heterogeneity will still exist within this

population of women. This may be mitigated by the large sample size and the

stratified randomisation of women to treatment according to age and study

site.

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INTRODUCTION

Data indicate that one in six couples worldwide will experience an infertility problem

at least once during their reproductive years.[1] In vitro fertilization (IVF) and

intracytoplasmic sperm injection (ICSI) are commonly employed methods of assisted

reproductive technology (ART) for the treatment of infertility. Outcome rates with

these techniques are comparable; in Europe in 2011, the mean rates of pregnancy per

embryo transfer were 33.2% and 31.6% following IVF and ICSI, respectively.[1]

Currently, two recombinant forms of human FSH (follitropin alfa and follitropin beta)

are commercially available for controlled ovarian stimulation.[2]

While a majority of patients treated with r-hFSH monotherapy for assisted

reproduction will benefit from treatment, as many as 26% will exhibit a poor ovarian

response (POR).[3] Although the ideal treatment protocol for patients with a poor

response to ovarian stimulation is yet to be identified, there is evidence to suggest that

supplementation of r-hFSH with recombinant human luteinizing hormone (r-hLH)

may be beneficial in this population of women. Hypothetically, this is attributed to the

widespread use of protocols utilizing r-hFSH (with no LH activity), accompanied by

observations of substantially lower LH concentrations than those observed with

previously used protocols and during the natural menstrual cycle.[4] Data from a

recently conducted meta-analysis including a total of 43 studies and 6443 patients

overall showed that the addition of r-hLH to r-hFSH was beneficial in poor

responders to ovarian stimulation (14 studies, n=1,179), resulting in a 30% relative

increase in the clinical pregnancy rate, compared with r-hFSH monotherapy.[5] The

supplementation of r-hFSH with r-hLH in poor responders also led to a significant

increase in the number of oocytes retrieved and the ongoing pregnancy rate.

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Moreover, a non-significant increase in the live birth rate was observed.[5] Data from

a meta-analysis performed prior to that of Lehert et al. showed that in patients of

advanced reproductive age (a population likely to comprise a larger proportion of

poor responders), the addition of r-hLH to r-hFSH improved the implantation and

clinical pregnancy rates, compared with r-hFSH monotherapy.[6]

Despite these findings, the use of r-hLH supplementation during controlled ovarian

stimulation remains a topic of ongoing debate. The results of several earlier meta-

analyses conducted in general ART populations indicate that supplementation with r-

hLH offers no benefit in terms of clinically significant endpoints in IVF/ICSI cycles,

including the number of oocytes retrieved, the number of mature oocytes and the rates

of implantation, pregnancy, miscarriage and/or live births.[4, 7-9] Reasons for this

may include insufficient numbers of patients, which is in contrast to the large number

of studies and patients analyzed by Lehert et al. in 2014. Given the conflicting data

regarding the use of LH supplementation during controlled ovarian stimulation,

particularly regarding the target population and optimal treatment agent, it is widely

agreed that well-designed, adequately powered, multicentre, randomised controlled

trials (RCTs) are warranted in this setting.[4, 7-10] To this end, the Efficacy and

Safety of Pergoveris®

in Assisted Reproductive Technology (ESPART) trial has been

initiated. The objective of the ESPART trial is to explore the possible superiority of a

fixed-dose combination of r-hFSH plus r-hLH in a 2:1 ratio over r-hFSH monotherapy

in patients with a POR, as per a definition aligned with the European Society of

Human Reproduction and Embryology (ESHRE) Bologna criteria.[11] The design of

and rationale for the ESPART trial are described in the current report.

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METHODS

Study design

ESPART is an ongoing Phase III, multicentre, single-blind, parallel-group RCT

(ClinicalTrials.gov identifier: NCT02047227; EudraCT Number: 2013-003817-16).

The ESPART trial, which is being conducted at more than 90 sites in 18 European

countries has been specifically designed to compare the efficacy and safety of

controlled ovarian stimulation with a fixed-dose combination of r-hFSH plus r-hLH in

a 2:1 ratio with r-hFSH monotherapy for multifollicular development in poor ovarian

responders, as per a definition aligned with the Bologna criteria. The study is being

performed in accordance with the clinical trial protocol, with the ethical principles

that have their origin in the Declaration of Helsinki, with the International Conference

on Harmonisation–Good Clinical Practice guidelines and all applicable regulatory

requirements. All participants in the ESPART study will provide written informed

consent prior to entry.

Study participants

In order to participate in the study, women will be required to meet the following

inclusion criteria: age 18 to <41 years; body mass index 18–30 kg/m2; eligible for

controlled ovarian stimulation and ART treatment (including ICSI); anticipated and/or

confirmed POR to stimulation, using criteria aligned with the 2011 ESHRE Bologna

criteria,[11] i.e. at least two of the following three features: advanced maternal age

[40–41 years]; a previous cycle with ≤3 oocytes retrieved with a conventional

stimulation protocol; and/or an abnormal ovarian reserve test [ORT] characterised by

an anti-Müllerian hormone level greater than or equal to the lower limit of assay

detection to 1.3 ng/mL [inclusive]; access to motile, ejaculatory sperm (including

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donated and/or cryopreserved sperm); and no treatment with clomiphene citrate or

gonadotropins for ≥1 month prior to screening. Specific exclusion criteria include:

primary ovarian failure; pre-implantation genetic screening or diagnosis; two episodes

of POR after maximal stimulation; history or presence of tumors of the hypothalamus

or pituitary gland; history or presence of ovarian enlargement or cysts of unknown

etiology; presence of an ovarian cyst >25 mm on the day of randomization; presence

of confirmed or suspected Grade III–IV endometriosis; presence of uni- or bilateral

hydrosalpinx; abnormal gynecological bleeding of undetermined origin; malformation

of the sexual organs incompatible with pregnancy; contraindication to being pregnant

and/or carrying a pregnancy to term; currently pregnant; presence of a clinically

significant concurrent medical condition (e.g. diabetes) that would compromise

subject safety or interfere with the trial assessments; known infection with human

immunodeficiency virus (HIV) or active hepatitis B or C virus (including in the male

partner); history or presence of ovarian, uterine or mammary cancer; known allergy or

hypersensitivity to human gonadotropin preparations or to compounds structurally

similar to any of the other medications administered during the trial; substance abuse

that would interfere with the trial conduct; use of testicular or epididymal sperm;

and/or participation in another ART clinical trial within the preceding 30 days.

Study treatments and interventions

Patients in the ESPART study will be enrolled for a maximum duration of 365 days,

involving 17 clinic visits. Following screening (visit 1), eligible patients will initiate

pituitary down-regulation (visit 2) with daily triptorelin acetate (Decapeptyl®

; Ferring

Pharmaceuticals, Saint-Prex, Switzerland) at a dose of 0.1 mg; treatment will be self-

administered via subcutaneous injection and will start on day 20–21 of a normal cycle

or on cycle day 3–4 of progesterone-induced menses in anovulatory or oligo-

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ovulatory patients. Within four days of confirmation of pituitary down-regulation

(serum estradiol level ≤50 pg/mL after ≥14 but ≤21 days of triptorelin acetate [visits

3a and 3b]) and following a negative pregnancy test, patients will be randomised (1:1)

to receive controlled ovarian stimulation with either a fixed-dose combination of r-

hFSH 300 IU plus r-hLH 150 IU (follitropin alfa and lutropin alfa in a 2:1 ratio;

Pergoveris®

; EMD Serono, Inc., Rockland, MA, USA) or r-hFSH 300 IU

monotherapy (follitropin alfa; GONAL-f®

; EMD Serono, Inc., Rockland, MA, USA)

(visit 4). Both treatment regimens, which will be administered concomitantly with

daily triptorelin acetate, will be delivered subcutaneously at approximately the same

time each day; study participants will be instructed on how to self-administer

treatment, with the first dose to be administered at the clinic under supervision.

Patients will be seen every 2–3 days from stimulation day 5–21 (visits 5–10). During

this time, adjustments in the dose of r-hFSH will be made if clinically required, as

monitored by study investigators; adjustments (increases or decreases) will be allowed

in 75 IU increments (with concomitant automatic adjustment of r-hLH in subjects

treated with combination treatment in order to maintain a r-hFSH:r-hLH ratio of 2:1).

The maximum daily dose of r-hFSH shall not exceed 450 IU. When follicle(s) reach a

mean diameter of 17–18 mm, patients will receive a single injection of recombinant

human chorionic gonadotropin (r-hCG; choriogonadotropin alfa; Ovidrel®

/Ovitrelle®

,

EMD Serono, Inc., Rockland, MA, USA) at a dose of 250 µg to induce final follicular

maturation (visit 11). Approximately 34–38 hours later oocytes will be retrieved

vaginally under ultrasound monitoring (visit 12) and IVF or ICSI will be performed.

Embryos (no more than three) will be transferred 2–3 days following oocyte retrieval

(visit 13). The procedures used for IVF, ICSI and embryo transfer as well as the total

number of embryos transferred will depend upon the study site’s standard practices

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and/or local and country-specific regulations. Support of the luteal phase will be

achieved using intravaginal 8% progesterone gel (Crinone®

; Fleet Laboratories Ltd.,

Watford, UK); treatment will be self-administered on a once-daily basis using single-

use pre-filled applicators containing a progesterone dose of 90 mg. Treatment will

start within 48 hours after oocyte retrieval and will continue for ≥7 weeks (unless

miscarriage occurs) in subjects with a clinical pregnancy.

Subjects will be discontinued from the trial in the following situations: a lack of

pituitary down-regulation within 21 days of triptorelin acetate treatment; a lack of an

appropriate response to controlled ovarian stimulation (i.e. no follicles ≥12 mm and

endometrial thickness ≤4 mm after 8 days of treatment and/or a clinically significant

decrease in estradiol levels for two consecutive days/visits); and an excessive

response to controlled ovarian stimulation (indicating a risk of ovarian

hyperstimulation syndrome).

Randomization (1:1) to r-hFSH plus r-hLH or r-hFSH monotherapy will be stratified

by study site and subject age (<35 years or ≥35 years). When a subject is eligible for

randomization, the unblinded personnel at each investigator’s site will contact an

interactive voice response system (Cenduit GmbH, Switzerland) and treatment will be

assigned accordingly. As per the single-blind nature of the study, investigators and

site personnel (e.g. assessing physicians, ultrasonographers, embryologists, etc.) will

remain blinded to the treatment regimen patients are receiving; trial nurses or

pharmacists will instruct subjects on the correct preparation, handling and storage of

all study treatments, including how to perform dose adjustments, if indicated. All

study medications will be packaged in secondary containers and will be labeled

specifically for the trial by a qualified packaging provider.

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Study objectives and endpoints

The primary objective of the study is to demonstrate the superiority of a fixed-dose

combination of r-hFSH plus r-hLH in a 2:1 ratio over r-hFSH monotherapy in patients

with a POR, as per a definition aligned with the ESHRE Bologna criteria. The

primary endpoint is the total number of retrieved oocytes per subject. Secondary

endpoints are as follows: ongoing pregnancy rate (percentage of subjects with an

ultrasound confirmation of ≥1 viable fetus [i.e. positive fetal heart beat] performed 10

± 1 weeks after embryo transfer [visit 16]); live birth rate (percentage of subjects with

≥1 live born neonate [visit 17]; embryo implantation rate (number of gestational sacs

divided by the number of embryos transferred per subject at 35–42 days post-r-hCG

administration [visit 15]); biochemical pregnancy rate (positive β-hCG result from a

serum pregnancy test performed 15–20 days post-r-hCG administration [visit 14]);

and clinical pregnancy rate (percentage of subjects with an ultrasound confirmation of

a gestational sac with or without fetal heart activity performed [visit 15]). Safety

endpoints include: incidence and severity of ovarian hyperstimulation syndrome

(OHSS; defined as the number of cases of OHSS during the ovarian stimulation

period and their severity as assessed by the investigator) [Visits 4–16]; incidence of

adverse events and serious adverse events (as assessed throughout the course of the

trial); and local tolerability, including expected injection site reactions (pain,

erythema, hematoma, swelling, and/or irritation at the injection site).

Statistical methods

Overall, 852 subjects are planned to be enrolled to detect a difference of one retrieved

oocyte between the two treatment arms, with a common standard deviation of 4.5.

Allowing for a drop-out rate of 10%, the total number of patients randomised to

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treatment is expected to be approximately 940, assuming an overall two-sided

significance level of 0.05 and 90% power to detect the stated difference.

Primary and secondary endpoints will be assessed in the modified intention-to-treat

(ITT) population. Subjects who do not undergo the oocyte retrieval process at visit 12

for other reasons (e.g. withdrawal of consent, lost to follow up), will have their

number of oocytes retrieved counted as ‘0’ for the analysis of the primary endpoint.

Safety endpoints will be assessed in the safety population, which will be defined as all

randomised subjects who receive ≥1 dose of r-hFSH plus r-hLH or r-hFSH.

Depending on the probability function of the data, the primary efficacy variable will

be analyzed including terms for treatment arm, site (or country or region), and age

category using either an analysis of variance (ANOVA) model on raw data (if data is

normally distributed) or using an a log-transformed model or Poisson regression

model (if data is not normally distributed).

Summary descriptive statistics will be used for all quantitative variables (e.g. number

of subjects, number of missing values/subjects, mean, standard deviation, minimum,

maximum, median, first quartile and third quartile. The frequency and percentage of

subjects and/or events will be calculated for all qualitative variables).

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DISCUSSION

It is widely anticipated that with continued changes in the demographics of childbirth,

an increasing proportion of women undergoing fertility treatment will exhibit a poor

response to ovarian stimulation. Identifying suitable interventions that will improve

outcomes in such women has proved challenging, owing to a lack of clarity about the

causes and mechanisms of a POR and to limitations in studies that have sought to

address this unmet clinical need; such limitations include small patient populations,

the use of diverse endpoints, inherent biases and/or a lack of consensus regarding the

definition of a POR.[11-13]

The ESPART trial is an ongoing Phase III, multicentre RCT that has been designed to

compare the efficacy and safety of controlled ovarian stimulation with a fixed-dose

combination of r-hFSH plus r-hLH in a 2:1 ratio against r-hFSH monotherapy for

multifollicular development in women with a POR, as per a definition aligned with

the ESHRE Bologna criteria. For a variety of compelling reasons, the ESPART study

is expected to generate meaningful results that will enhance the overall quality of

research in the field of assisted reproduction, improve treatment choices, and benefit

patients. Firstly, it is the first Phase III study with a superiority design to evaluate the

possible advantage of supplemental r-hLH for controlled ovarian stimulation in

women with a POR. Secondly, it likely represents the largest trial of its kind in

women with or at risk of a POR; indeed, to the best of the authors’ knowledge, the

ESPART trial will include more than double the number of patients included in any

other RCT that has compared r-hFSH plus r-hLH with r-hFSH monotherapy for

multifollicular development in women undergoing IVF and/or ICSI, including RCTs

in women with a POR.[5] Lastly, it uses a POR definition that is aligned with the

ESHRE Bologna criteria.[11]

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The ESHRE Bologna criteria were published in 2011 in an attempt to standardise the

definition of a POR in a simple and reproducible manner and to generate more

homogeneous populations in which new treatment strategies could be tested and

subsequently compared.[11] Since becoming available, the ESHRE Bologna criteria

have been used to define women with a POR in several studies.[14-18] According to

the criteria, a POR is defined as the presence of at least two of the following three

features: advanced maternal age (≥40 years) or any other risk factor for POR; a

previous POR (≤3 oocytes with a conventional stimulation protocol); and/or an ORT

(i.e. antral follicle count <5–7 or an anti-Müllerian hormone level <0.5–1.1 ng/mL).

Women can also be considered poor responders in the absence of advanced maternal

age or an abnormal ORT if they have experienced two episodes of POR after maximal

stimulation.

It should be stressed that the definition of a POR in the current study is aligned with,

but not identical to the definition of a POR according to the ESHRE Bologna criteria

so as to reduce heterogeneity of the patient population. Firstly, a subset of patients

qualified for POR based on the existence of advanced maternal age will not include

patients aged >41 years (inclusive). Secondly, the presence of any other risk factor for

POR is not an inclusion criterion in the ESPART study. Thirdly, an abnormal ORT

will be based on the results of an anti-Müllerian hormone level greater than or equal

to the lower limit of assay detection to 1.3 ng/mL inclusive. Lastly, women will not be

included (and indeed will be specifically excluded) if they have two episodes of POR

after maximal stimulation. Furthermore, subjective criteria such as antral follicle

count cannot be appropriately controlled and lack the reproducibility of quantifiable

measurements such as serum AMH.

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Although the ESHRE Bologna criteria establish a concept of minimum qualifying

criteria for a POR, clinical heterogeneity, particularly in terms of baseline

characteristics and clinical prognosis, is still possible within this population of

women[19] and, by definition, within women in the current study. The suggested

selection of patients in ESPART is intended to reduce such heterogeneity, which will

also be mitigated by the large sample size and the stratified randomization of women

to treatment by age and investigation site.

As has been previously described, the use of LH supplementation during IVF/ICSI in

women undergoing controlled ovarian stimulation is widely debated in the

literature.[4-10] In particular, the population of women in whom LH supplementation

may be beneficial remains a matter of debate. In this regard, the results of the recent

meta-analysis by Lehert et al. (2014) suggest that the addition of r-hLH to r-hFSH

may be beneficial in women with a POR.[5] In order to confirm the results of this

meta-analysis with a well-controlled, randomised phase III trial, this ESPART study

was designed to answer the question of whether the addition of LH to controlled

ovarian stimulation with FSH results in better cycle outcomes. With this in mind, and

in order to demonstrate the additional benefit of adding LH to FSH in controlled

ovarian stimulation, the clear comparator for the study is r-FSH alone.

Supplementation with r-hLH will be initiated on Day 1 of stimulation, which is in

contrast with other studies that have initiated LH on stimulation Days 6–8 in patients

with a POR.[20-24] The administration of r-hLH from stimulation Day 1 is

considered appropriate given that LH plays a key role in gonadal function from the

early and mid-follicular phases, through to oocyte maturation and follicular

luteinization, and due to the fact that the LH receptor is present in follicles as small as

6 mm.[25, 26]

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Finally, we should mention that the standard treatment for multi-follicular

development in general ART populations involves the administration of r-hFSH at a

dose of 150–225 IU for the first days of treatment,[27] but the starting dose of r-hFSH

in the ESPART study will be 300 IU; the higher starting dose of r-hFSH used in the

current study is consistent with the current clinical practice of using increased doses

of gonadotropins in women with a POR.[28]

The ESPART trial was initiated in January 2014. Based on previous analyses, it is

anticipated that the study results will show that a fixed-dose combination of r-hFSH

and r-hLH in a 2:1 ratio during controlled ovarian stimulation is superior to r-hFSH

monotherapy in women with a POR. The clinical importance of the study is

considered to be high, owing to the paucity of well-designed, adequately powered,

multicentre RCTs that have investigated the efficacy and safety of supplemental r-

hLH in women undergoing controlled ovarian stimulation. Furthermore, because the

study uses a POR definition that is aligned with the Bologna criteria, it supports the

aim of the ESHRE to create more homogeneous populations in which new treatment

strategies for POR can be tested and subsequently compared.

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AUTHORS’ CONTRIBUTIONS

PH participated in the conception and design of the study as well as the acquisition of

data. PH will participate in the analysis and interpretation of final data as well as

drafting of and acceptance of the final manuscript. RF participated in the conception

and design of the study and will participate in the analysis and interpretation of the

final data. JS participated in the conception and design of the study and will

participate in the analysis and interpretation of the final data. All authors critically

revised the current work for important intellectual content and gave final approval of

the version of the publication to be published. All authors have agreed to be

accountable for all aspects of the work in ensuring that questions related to the

accuracy or integrity of any part of it are appropriately investigated and resolved.

ACKNOWLEDGEMENTS

The authors would like to thank Amy Evans of inScience Communications, Springer

Healthcare, for providing medical writing support in the preparation of this

manuscript. This support was funded by Merck KGaA Darmstadt.

FUNDING

This study was funded by Merck KGaA Darmstadt.

COMPETING INTERESTS

P. Humaidan and R. Fischer have no competing interests related to this manuscript. J.

Schertz is an employee of EMD Serono Research & Development Institute, Inc..

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REFERENCES

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(accessed 19 December 2014).

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'good' responders using a standard buserelin/human menopausal

gonadotrophin regime for in-vitro fertilization. Hum Reprod 1991;6(7):918-

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4. Baruffi RL, Mauri AL, Petersen CG, et al. Recombinant LH supplementation to

recombinant FSH during induced ovarian stimulation in the GnRH-antagonist

protocol: a meta-analysis. Reprod Biomed Online 2007;14(1):14-25.

5. Lehert P, Kolibianakis EM, Venetis CA, et al. Recombinant human follicle-

stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-

hFSH alone for ovarian stimulation during assisted reproductive technology:

systematic review and meta-analysis. Reprod Biol Endocrinol 2014;12:17.

6. Hill MJ, Levens ED, Levy G, et al. The use of recombinant luteinizing hormone in

patients undergoing assisted reproductive techniques with advanced

reproductive age: a systematic review and meta-analysis. Fertil Steril

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7. Oliveira JB, Mauri AL, Petersen CG, et al. Recombinant luteinizing hormone

supplementation to recombinant follicle-stimulation hormone during induced

ovarian stimulation in the GnRH-agonist protocol: a meta-analysis. J Assist

Reprod Genet 2007;24(2-3):67-75.

8. Kolibianakis EM, Kalogeropoulou L, Griesinger G, et al. Among patients treated

with FSH and GnRH analogues for in vitro fertilization, is the addition of

recombinant LH associated with the probability of live birth? A systematic

review and meta-analysis. Hum Reprod Update 2007;13(5):445-52.

9. Xiong Y, Bu Z, Dai W, et al. Recombinant luteinizing hormone supplementation in

women undergoing in vitro fertilization/ intracytoplasmic sperm injection with

gonadotropin releasing hormone antagonist protocol: a systematic review and

meta-analysis. Reprod Biol Endocrinol 2014;12:109.

10. Legro RS, Kunselman AR. A good meta-analysis is hard to find. Fertil Steril

2012;97(5):1048-9.

11. Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition

of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna

criteria. Hum Reprod 2011;26(7):1616-24.

12. Polyzos NP, Devroey P. A systematic review of randomized trials for the

treatment of poor ovarian responders: is there any light at the end of the

tunnel? Fertil Steril 2011;96(5):1058-61 e7.

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13. Ubaldi F, Vaiarelli A, D'Anna R, et al. Management of poor responders in IVF: is

there anything new? Biomed Res Int 2014;2014:352098.

14. Ferraretti AP, Gianaroli L, Motrenko T, et al. LH pretreatment as a novel strategy

for poor responders. Biomed Res Int 2014;2014:926172.

15. Polyzos NP, Blockeel C, Verpoest W, et al. Live birth rates following natural

cycle IVF in women with poor ovarian response according to the Bologna


16. Polyzos NP, De Vos M, Corona R, et al. Addition of highly purified HMG after

corifollitropin alfa in antagonist-treated poor ovarian responders: a pilot study.

Hum Reprod 2013;28(5):1254-60.

17. Xu B, Li Z, Yue J, et al. Effect of dehydroepiandrosterone administration in

patients with poor ovarian response according to the Bologna criteria. PloS

one 2014;9(6):e99858.

18. Jirge PR, Chougule SM, Gavali VG, et al. Impact of dehydroepiandrosterone on

clinical outcome in poor responders: A pilot study in women undergoing in

vitro fertilization, using bologna criteria. J Hum Reprod Sci 2014;7(3):175-80.

19. Papathanasiou A. Implementing the ESHRE 'poor responder' criteria in research

studies: methodological implications. Hum Reprod 2014;29(9):1835-8.

20. De Placido G, Alviggi C, Perino A, et al. Recombinant human LH

supplementation versus recombinant human FSH (rFSH) step-up protocol

during controlled ovarian stimulation in normogonadotrophic women with

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initial inadequate ovarian response to rFSH. A multicentre, prospective,

randomized controlled trial. Hum Reprod 2005;20(2):390-6.

21. Ruvolo G, Bosco L, Pane A, et al. Lower apoptosis rate in human cumulus cells

after administration of recombinant luteinizing hormone to women undergoing

ovarian stimulation for in vitro fertilization procedures. Fertil Steril

2007;87(3):542-6.

22. Barrenetxea G, Agirregoikoa JA, Jimenez MR, et al. Ovarian response and

pregnancy outcome in poor-responder women: a randomized controlled trial

on the effect of luteinizing hormone supplementation on in vitro fertilization

cycles. Fertil Steril 2008;89(3):546-53.

23. Brunet C, Dechanet C, Reyftmann I, et al. Impact of r-LH supplementation on the

estradiol level during ovarian stimulation for IVF: a randomized prospective

study. Fertil Steril 2009;92(3 (Suppl)):S240.

24. Lisi F, Rinaldi L, Fishel S, et al. Better implantation rate overimposing

recombinant LH (Luveris) on recombinant FSH (Gonal F) in multiple

follicular stimulation for IVF. Hum Reprod 2002;17(Suppl 1):134.

25. Buhler KF, Fischer R. Recombinant human LH supplementation versus

supplementation with urinary hCG-based LH activity during controlled

ovarian stimulation in the long GnRH-agonist protocol: a matched case-

control study. Gynecol Endocrinol 2012;28(5):345-50.

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26. Jeppesen JV, Kristensen SG, Nielsen ME, et al. LH-receptor gene expression in

human granulosa and cumulus cells from antral and preovulatory follicles. J

Clin Endocrinol Metab 2012;97(8):E1524-31.

27. Electronic Medicines Compendium. GONAL-f 450 IU (33 mcg) pen Summary of

Product Characteristics (Merck Serono). 2014.

http://www.medicines.org.uk/emc/medicine/14384 (accessed 17 December

2014).

28. IVF Worldwide. Survey results: poor responders: How to define, diagnose and

treat? Results of 124,700 IVF treatment cycles (196 centres from 45 countries)

(Leong, M. and Patrizio, P.). 2010. http://www.ivf-worldwide.com/news/276-

newsletter-august-82010.html (accessed 17 December 2014).

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CONSORT 2010 checklist Page 1

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2–4

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 5–7

2b Specific objectives or hypotheses 7

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 7 and 9

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons N/A

Participants 4a Eligibility criteria for participants 8–9

4b Settings and locations where the data were collected 7

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

9–10

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

11

6b Any changes to trial outcomes after the trial commenced, with reasons N/A

Sample size 7a How sample size was determined 12

7b When applicable, explanation of any interim analyses and stopping guidelines N/A

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 11

8b Type of randomisation; details of any restriction (such as blocking and block size) 11

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned TBC

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions TBC

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 11

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assessing outcomes) and how

11b If relevant, description of the similarity of interventions N/A

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 12

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses N/A

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

N/A

13b For each group, losses and exclusions after randomisation, together with reasons N/A

Recruitment 14a Dates defining the periods of recruitment and follow-up N/A

14b Why the trial ended or was stopped N/A

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group N/A

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

N/A

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

N/A

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended N/A

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

N/A

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) N/A

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 15

Generalisability 21 Generalisability (external validity, applicability) of the trial findings N/A

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence N/A

Other information

Registration 23 Registration number and name of trial registry 7

Protocol 24 Where the full trial protocol can be accessed, if available

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 17

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

Comment [Anon1]: A complete protocol will not be publically available as it is deemed to be proprietary information. A protocol synopsis in the form of this publication and as posted on ClinicalTrials.gov is deemed sufficient.

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Efficacy and Safety of Pergoveris® in Assisted Reproductive Technology – ESPART: rationale and design of a randomised

controlled trial in poor ovarian responders undergoing IVF/ICSI treatment

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008297.R1

Article Type: Protocol

Date Submitted by the Author: 29-May-2015

Complete List of Authors: Humaidan, Peter; The Fertility Clinic, Skive Regional Hospital Schertz, Joan; EMD Serono Research & Development Institute, Fertility Global Clinical Development Unit Fischer, Robert; MVZ Fertility Center Hamburg GmbH,

<b>Primary Subject Heading</b>:

Reproductive medicine

Secondary Subject Heading: Reproductive medicine

Keywords: REPRODUCTIVE MEDICINE, Subfertility < GYNAECOLOGY, Clinical trials < THERAPEUTICS


BMJ Open on O

ctober 26, 2020 by guest. Protected by copyright.

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Efficacy and Safety of Pergoveris® in

Assisted Reproductive Technology – ESPART: rationale and design of a randomised controlled trial in poor ovarian responders undergoing IVF/ICSI treatment

Running title: RCT of r-hFSH with/without r-hLH in POR patients

P. Humaidan,1* J. Schertz,

2 R. Fischer

3

1The Fertility Clinic, Skive Regional Hospital, Faculty of Health, Aarhus University,

7800 Skive, Denmark; 2Fertility Global Clinical Development Unit, EMD Serono

Research & Development Institute, Inc., Billerica, MA 01821, USA; 3Fertility Center

Hamburg, 20095 Hamburg, Germany

*Corresponding author:

Peter Humaidan, Professor, DMSc, The Fertility Clinic, Skive Regional Hospital,

Faculty of Health, Aarhus University, Resenvej 25, 7800 Skive, Denmark

Tel.: + 45 23 81 59 91; E-mail: [email protected]

Keywords: assisted reproductive technologies – Bologna criteria – poor ovarian

response – recombinant human follicle-stimulating hormone – recombinant human

luteinizing hormone

Word count (excluding title page, abstract and references): 3289

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ABSTRACT

Introduction: The results of a recent meta-analysis showed that adding recombinant

human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating

hormone (r-hFSH) for ovarian stimulation was beneficial in poor responders, resulting

in a 30% relative increase in the clinical pregnancy rate compared with r-hFSH

monotherapy. However, a limitation of the meta-analysis was that the included studies

used heterogeneous definitions of poor ovarian response (POR). Furthermore, the use

of r-hLH supplementation during ovarian stimulation is a topic of ongoing debate and

well-designed, adequately powered, multicentre, randomised controlled trials in this

setting are warranted. Therefore, the objective of the ESPART trial is to explore the

possible superiority of a fixed-dose combination of r-hFSH plus r-hLH over r-hFSH

monotherapy in patients with POR, as per a definition aligned with the European

Society of Human Reproduction and Embryology (ESHRE) Bologna criteria.

Methods and analysis: Phase III, randomised, single-blind, parallel-group trial in

women undergoing in vitro fertilization and/or intracytoplasmic sperm injection.

Approximately 946 women aged 18– <41 years from 18 countries will be randomised

(1:1) to receive a fixed-dose combination of r-hFSH plus r-hLH in a 2:1 ratio

(Pergoveris®

) or r-hFSH monotherapy (GONAL-f®

). The primary endpoint is the total

number of retrieved oocytes per subject. Secondary endpoints include: ongoing

pregnancy rate, live birth rate, implantation rate, biochemical pregnancy rate and

clinical pregnancy rate. Safety endpoints include: incidence and severity of ovarian

hyperstimulation syndrome and of adverse events and serious adverse events.

Ethics and dissemination: The study will be performed in accordance with the

ethical principles that have their origin in the Declaration of Helsinki, with the

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International Conference on Harmonisation–Good Clinical Practice guidelines and all

applicable regulatory requirements. All participants will provide written informed

consent prior to entry. The results of this study will be publically disseminated.

Trial registration numbers: ClinicalTrials.gov identifier: NCT02047227; EudraCT

Number: 2013-003817-16; Clinical Trial Protocol Number: EMR200061-005 Version

3.0, 15 April 2014

Strengths and limitations of this study:

• To the authors’ knowledge, the ESPART study will be the largest randomised

controlled trial (RCT) conducted in women with poor ovarian response (POR).

Furthermore, it is the first Phase III study with a superiority design that will

evaluate the possible advantage of the addition of r-hLH to r-hFSH for

controlled ovarian stimulation in this patient population. The ESPART study

fulfills the criteria of a robust, well-designed RCT, which uses a definition of

POR that is consistent with the Bologna criteria.

• Although the ESPART study will recruit women with POR, as aligned with

the Bologna criteria, clinical heterogeneity will still exist within this

population of women. This may be mitigated by the large sample size and the

stratified randomisation of women to treatment according to age and study

site.

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INTRODUCTION

Data indicate that one in six couples worldwide will experience an infertility problem

at least once during their reproductive years.[1] In vitro fertilization (IVF) and

intracytoplasmic sperm injection (ICSI) are commonly employed methods of assisted

reproductive technology (ART) for the treatment of infertility. Outcome rates with

these techniques are comparable; in Europe in 2011, the mean rates of pregnancy per

embryo transfer were 33.2% and 31.6% following IVF and ICSI, respectively.[1]

Currently, two recombinant forms of human FSH (follitropin alfa and follitropin beta)

are commercially available for controlled ovarian stimulation.[2]

While a majority of patients treated with r-hFSH monotherapy for assisted

reproduction will benefit from treatment, as many as 26% will exhibit a poor ovarian

response (POR).[3] Although the ideal treatment protocol for patients with a poor

response to ovarian stimulation is yet to be identified, there is evidence to suggest that

supplementation of r-hFSH with recombinant human luteinizing hormone (r-hLH)

may be beneficial in this population of women. Hypothetically, this is attributed to the

widespread use of protocols utilizing r-hFSH (with no LH activity), accompanied by

observations of substantially lower LH concentrations than those observed with

previously used protocols and during the natural menstrual cycle.[4] Data from a

recently conducted meta-analysis including a total of 43 studies and 6443 patients

overall showed that the addition of r-hLH to r-hFSH was beneficial in poor

responders to ovarian stimulation (14 studies, n=1,179), resulting in a 30% relative

increase in the clinical pregnancy rate, compared with r-hFSH monotherapy.[5] The

supplementation of r-hFSH with r-hLH in poor responders also led to a significant

increase in the number of oocytes retrieved and the ongoing pregnancy rate.

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Moreover, a non-significant increase in the live birth rate was observed.[5] Data from

a meta-analysis performed prior to that of Lehert et al. showed that in patients of

advanced reproductive age (a population likely to comprise a larger proportion of

poor responders), the addition of r-hLH to r-hFSH improved the implantation and

clinical pregnancy rates, compared with r-hFSH monotherapy.[6]

Despite these findings, the use of r-hLH supplementation during controlled ovarian

stimulation remains a topic of ongoing debate. The results of several earlier meta-

analyses conducted in general ART populations indicate that supplementation with r-

hLH offers no benefit in terms of clinically significant endpoints in IVF/ICSI cycles,

including the number of oocytes retrieved, the number of mature oocytes and the rates

of implantation, pregnancy, miscarriage and/or live births.[4, 7-9] Reasons for this

may include insufficient numbers of patients, which is in contrast to the large number

of studies and patients analyzed by Lehert et al. in 2014. Given the conflicting data

regarding the use of LH supplementation during controlled ovarian stimulation,

particularly regarding the target population and optimal treatment agent, it is widely

agreed that well-designed, adequately powered, multicentre, randomised controlled

trials (RCTs) are warranted in this setting.[4, 7-10] To this end, the Efficacy and

Safety of Pergoveris®

in Assisted Reproductive Technology (ESPART) trial has been

initiated. The objective of the ESPART trial is to explore the possible superiority of a

fixed-dose combination of r-hFSH plus r-hLH in a 2:1 ratio over r-hFSH monotherapy

in patients with a POR, as per a definition aligned with the European Society of

Human Reproduction and Embryology (ESHRE) Bologna criteria.[11] The design of

and rationale for the ESPART trial are described in the current report.

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METHODS

Study design

ESPART is an ongoing Phase III, multicentre, single-blind, parallel-group RCT

(ClinicalTrials.gov identifier: NCT02047227; EudraCT Number: 2013-003817-16).

The ESPART trial, which is being conducted at more than 90 sites in 18 European

countries has been specifically designed to compare the efficacy and safety of

controlled ovarian stimulation with a fixed-dose combination of r-hFSH plus r-hLH in

a 2:1 ratio with r-hFSH monotherapy for multifollicular development in poor ovarian

responders, as per a definition aligned with the Bologna criteria. The study is being

performed in accordance with the clinical trial protocol, with the ethical principles

that have their origin in the Declaration of Helsinki, with the International Conference

on Harmonisation–Good Clinical Practice guidelines and all applicable regulatory

requirements. All participants in the ESPART study will provide written informed

consent prior to entry.

Study participants

In order to participate in the study, women will be required to meet the following

inclusion criteria: age 18 to <41 years; body mass index 18–30 kg/m2; eligible for

controlled ovarian stimulation and ART treatment (including ICSI); anticipated and/or

confirmed POR to stimulation, using criteria aligned with the 2011 ESHRE Bologna

criteria,[11] i.e. at least two of the following three features: advanced maternal age

[40–41 years]; a previous cycle with ≤3 oocytes retrieved with a conventional

stimulation protocol; and/or an abnormal ovarian reserve test [ORT] characterised by

an anti-Müllerian hormone level greater than or equal to the lower limit of assay

detection to 1.3 ng/mL [inclusive]; access to motile, ejaculatory sperm (including

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donated and/or cryopreserved sperm); and no treatment with clomiphene citrate or

gonadotropins for ≥1 month prior to screening. Specific exclusion criteria include:

primary ovarian failure; pre-implantation genetic screening or diagnosis; two episodes

of POR after maximal stimulation; history or presence of tumors of the hypothalamus

or pituitary gland; history or presence of ovarian enlargement or cysts of unknown

etiology; presence of an ovarian cyst >25 mm on the day of randomization; presence

of confirmed or suspected Grade III–IV endometriosis; presence of uni- or bilateral

hydrosalpinx; abnormal gynecological bleeding of undetermined origin; malformation

of the sexual organs incompatible with pregnancy; contraindication to being pregnant

and/or carrying a pregnancy to term; currently pregnant; presence of a clinically

significant concurrent medical condition (e.g. diabetes) that would compromise

subject safety or interfere with the trial assessments; known infection with human

immunodeficiency virus (HIV) or active hepatitis B or C virus (including in the male

partner); history or presence of ovarian, uterine or mammary cancer; known allergy or

hypersensitivity to human gonadotropin preparations or to compounds structurally

similar to any of the other medications administered during the trial; substance abuse

that would interfere with the trial conduct; use of testicular or epididymal sperm;

and/or participation in another ART clinical trial within the preceding 30 days.

Study treatments and interventions

Patients in the ESPART study will be enrolled for a maximum duration of 365 days,

involving 17 clinic visits. Following screening (visit 1), eligible patients will initiate

pituitary down-regulation (visit 2) with daily triptorelin acetate (Decapeptyl®

; Ferring

Pharmaceuticals, Saint-Prex, Switzerland) at a dose of 0.1 mg; treatment will be self-

administered via subcutaneous injection and will start on day 20–21 of a normal cycle

or on cycle day 3–4 of progesterone-induced menses in anovulatory or oligo-

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ovulatory patients. Within four days of confirmation of pituitary down-regulation

(serum estradiol level ≤50 pg/mL after ≥14 but ≤21 days of triptorelin acetate [visits

3a and 3b]) and following a negative pregnancy test, patients will be randomised (1:1)

to receive controlled ovarian stimulation with either a fixed-dose combination of r-

hFSH 300 IU plus r-hLH 150 IU (follitropin alfa and lutropin alfa in a 2:1 ratio;

Pergoveris®

; EMD Serono, Inc., Rockland, MA, USA) or r-hFSH 300 IU

monotherapy (follitropin alfa; GONAL-f®

; EMD Serono, Inc., Rockland, MA, USA)

(visit 4). Both treatment regimens, which will be administered concomitantly with

daily triptorelin acetate, will be delivered subcutaneously at approximately the same

time each day; study participants will be instructed on how to self-administer

treatment, with the first dose to be administered at the clinic under supervision.

Patients will be seen every 2–3 days from stimulation day 5–21 (visits 5–10). During

this time, adjustments in the dose of r-hFSH will be made if clinically required, as

monitored by study investigators; adjustments (increases or decreases) will be allowed

in 75 IU increments (with concomitant automatic adjustment of r-hLH in subjects

treated with combination treatment in order to maintain a r-hFSH:r-hLH ratio of 2:1).

The maximum daily dose of r-hFSH shall not exceed 450 IU. When follicle(s) reach a

mean diameter of 17–18 mm, patients will receive a single injection of recombinant

human chorionic gonadotropin (r-hCG; choriogonadotropin alfa; Ovidrel®

/Ovitrelle®

,

EMD Serono, Inc., Rockland, MA, USA) at a dose of 250 µg to induce final follicular

maturation (visit 11). Approximately 34–38 hours later oocytes will be retrieved

vaginally under ultrasound monitoring (visit 12) and IVF or ICSI will be performed.

Embryos (no more than three) will be transferred 2–3 days following oocyte retrieval

(visit 13). The procedures used for IVF, ICSI and embryo transfer as well as the total

number of embryos transferred will depend upon the study site’s standard practices

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and/or local and country-specific regulations. Support of the luteal phase will be

achieved using intravaginal 8% progesterone gel (Crinone®

; Fleet Laboratories Ltd.,

Watford, UK); treatment will be self-administered on a once-daily basis using single-

use pre-filled applicators containing a progesterone dose of 90 mg. Treatment will

start within 48 hours after oocyte retrieval and will continue for ≥7 weeks (unless

miscarriage occurs) in subjects with a clinical pregnancy.

Subjects will be discontinued from the trial in the following situations: a lack of

pituitary down-regulation within 21 days of triptorelin acetate treatment; a lack of an

appropriate response to controlled ovarian stimulation (i.e. no follicles ≥12 mm and

endometrial thickness ≤4 mm after 8 days of treatment and/or a clinically significant

decrease in estradiol levels for two consecutive days/visits); and an excessive

response to controlled ovarian stimulation (indicating a risk of ovarian

hyperstimulation syndrome).

Randomization (1:1) to r-hFSH plus r-hLH or r-hFSH monotherapy will be stratified

by study site and subject age (<35 years or ≥35 years). When a subject is eligible for

randomization, the unblinded personnel at each investigator’s site will contact an

interactive voice response system (Cenduit GmbH, Switzerland) and treatment will be

assigned accordingly. As per the single-blind nature of the study, investigators and

site personnel (e.g. assessing physicians, ultrasonographers, embryologists, etc.) will

remain blinded to the treatment regimen patients are receiving; trial nurses or

pharmacists will instruct subjects on the correct preparation, handling and storage of

all study treatments, including how to perform dose adjustments, if indicated. All

study medications will be packaged in secondary containers and will be labeled

specifically for the trial by a qualified packaging provider.

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Study objectives and endpoints

The primary objective of the study is to demonstrate the superiority of a fixed-dose

combination of r-hFSH plus r-hLH in a 2:1 ratio over r-hFSH monotherapy in patients

with a POR, as per a definition aligned with the ESHRE Bologna criteria. The

primary endpoint is the total number of retrieved oocytes per subject. Secondary

endpoints are as follows: ongoing pregnancy rate (percentage of subjects with an

ultrasound confirmation of ≥1 viable fetus [i.e. positive fetal heart beat] performed 10

± 1 weeks after embryo transfer [visit 16]); live birth rate (percentage of subjects with

≥1 live born neonate [visit 17]; embryo implantation rate (number of gestational sacs

divided by the number of embryos transferred per subject at 35–42 days post-r-hCG

administration [visit 15]); biochemical pregnancy rate (positive β-hCG result from a

serum pregnancy test performed 15–20 days post-r-hCG administration [visit 14]);

and clinical pregnancy rate (percentage of subjects with an ultrasound confirmation of

a gestational sac with or without fetal heart activity performed [visit 15]). Safety

endpoints include: incidence and severity of ovarian hyperstimulation syndrome

(OHSS; defined as the number of cases of OHSS during the ovarian stimulation

period and their severity as assessed by the investigator) [Visits 4–16]; incidence of

adverse events and serious adverse events (as assessed throughout the course of the

trial); and local tolerability, including expected injection site reactions (pain,

erythema, hematoma, swelling, and/or irritation at the injection site).

Statistical methods

Overall, 852 subjects are planned to be enrolled to detect a difference of one retrieved

oocyte between the two treatment arms, with a common standard deviation of 4.5.

Allowing for a drop-out rate of 10%, the total number of patients randomised to

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treatment is expected to be approximately 940, assuming an overall two-sided

significance level of 0.05 and 90% power to detect the stated difference. A total of

1365 subjects are expected to be screened to achieve a sample size of approximately

940 randomised patients.

Primary and secondary endpoints will be assessed in the modified intention-to-treat

(ITT) population. Subjects who do not undergo the oocyte retrieval process at visit 12

for other reasons (e.g. withdrawal of consent, lost to follow up), will have their

number of oocytes retrieved counted as ‘0’ for the analysis of the primary endpoint.

Safety endpoints will be assessed in the safety population, which will be defined as all

randomised subjects who receive ≥1 dose of r-hFSH plus r-hLH or r-hFSH.

Depending on the distribution of the data, the primary efficacy variable will be

analyzed using either an analysis of variance (ANOVA) model (if the data is normally

distributed) or a Poisson regression model (if the data is not normally distributed).

Both models will include terms for treatment arm, site (or country or region), and age

category.

Summary descriptive statistics will be used for all quantitative variables (e.g. number

of subjects, number of missing values/subjects, mean, standard deviation, minimum,

maximum, median, first quartile and third quartile. The frequency and percentage of

subjects and/or events will be calculated for all qualitative variables).

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DISCUSSION

It is widely anticipated that with continued changes in the demographics of childbirth,

an increasing proportion of women undergoing fertility treatment will exhibit a poor

response to ovarian stimulation. Identifying suitable interventions that will improve

outcomes in such women has proved challenging, owing to a lack of clarity about the

causes and mechanisms of a POR and to limitations in studies that have sought to

address this unmet clinical need; such limitations include small patient populations,

the use of diverse endpoints, inherent biases and/or a lack of consensus regarding the

definition of a POR.[11-13]

The ESPART trial is an ongoing Phase III, multicentre RCT that has been designed to

compare the efficacy and safety of controlled ovarian stimulation with a fixed-dose

combination of r-hFSH plus r-hLH in a 2:1 ratio against r-hFSH monotherapy for

multifollicular development in women with a POR, as per a definition aligned with

the ESHRE Bologna criteria. For a variety of compelling reasons, the ESPART study

is expected to generate meaningful results that will enhance the overall quality of

research in the field of assisted reproduction, improve treatment choices, and benefit

patients. Firstly, it is the first Phase III study with a superiority design to evaluate the

possible advantage of supplemental r-hLH for controlled ovarian stimulation in

women with a POR. Secondly, it likely represents the largest trial of its kind in

women with or at risk of a POR; indeed, to the best of the authors’ knowledge, the

ESPART trial will include more than double the number of patients included in any

other RCT that has compared r-hFSH plus r-hLH with r-hFSH monotherapy for

multifollicular development in women undergoing IVF and/or ICSI, including RCTs

in women with a POR.[5] Lastly, it uses a POR definition that is aligned with the

ESHRE Bologna criteria.[11]

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The ESHRE Bologna criteria were published in 2011 in an attempt to standardise the

definition of a POR in a simple and reproducible manner and to generate more

homogeneous populations in which new treatment strategies could be tested and

subsequently compared.[11] Since becoming available, the ESHRE Bologna criteria

have been used to define women with a POR in several studies.[14-18] According to

the criteria, a POR is defined as the presence of at least two of the following three

features: advanced maternal age (≥40 years) or any other risk factor for POR; a

previous POR (≤3 oocytes with a conventional stimulation protocol); and/or an ORT

(i.e. antral follicle count <5–7 or an anti-Müllerian hormone level <0.5–1.1 ng/mL).

Women can also be considered poor responders in the absence of advanced maternal

age or an abnormal ORT if they have experienced two episodes of POR after maximal

stimulation.

It should be stressed that the definition of a POR in the current study is aligned with,

but not identical to the definition of a POR according to the ESHRE Bologna criteria

so as to reduce heterogeneity of the patient population. Firstly, a subset of patients

qualified for POR based on the existence of advanced maternal age will not include

patients aged >41 years (inclusive). Secondly, the presence of any other risk factor for

POR is not an inclusion criterion in the ESPART study. Thirdly, an abnormal ORT

will be based on the results of an anti-Müllerian hormone level greater than or equal

to the lower limit of assay detection to 1.3 ng/mL inclusive. Lastly, women will not be

included (and indeed will be specifically excluded) if they have two episodes of POR

after maximal stimulation. Furthermore, subjective criteria such as antral follicle

count cannot be appropriately controlled and lack the reproducibility of quantifiable

measurements such as serum AMH.

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Although the ESHRE Bologna criteria establish a concept of minimum qualifying

criteria for a POR, clinical heterogeneity, particularly in terms of baseline

characteristics and clinical prognosis, is still possible within this population of

women[19] and, by definition, within women in the current study. The suggested

selection of patients in ESPART is intended to reduce such heterogeneity, which will

also be mitigated by the large sample size and the stratified randomization of women

to treatment by age and investigation site.

As has been previously described, the use of LH supplementation during IVF/ICSI in

women undergoing controlled ovarian stimulation is widely debated in the

literature.[4-10] In particular, the population of women in whom LH supplementation

may be beneficial remains a matter of debate. In this regard, the results of the recent

meta-analysis by Lehert et al. (2014) suggest that the addition of r-hLH to r-hFSH

may be beneficial in women with a POR.[5] In order to confirm the results of this

meta-analysis with a well-controlled, randomised phase III trial, this ESPART study

was designed to answer the question of whether the addition of LH to controlled

ovarian stimulation with FSH results in better cycle outcomes. With this in mind, and

in order to demonstrate the additional benefit of adding LH to FSH in controlled

ovarian stimulation, the clear comparator for the study is r-FSH alone.

Supplementation with r-hLH will be initiated on Day 1 of stimulation, which is in

contrast with other studies that have initiated LH on stimulation Days 6–8 in patients

with a POR.[20-24] The administration of r-hLH from stimulation Day 1 is

considered appropriate given that LH plays a key role in gonadal function from the

early and mid-follicular phases, through to oocyte maturation and follicular

luteinization, and due to the fact that the LH receptor is present in follicles as small as

6 mm.[25, 26]

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Finally, we should mention that the standard treatment for multi-follicular

development in general ART populations involves the administration of r-hFSH at a

dose of 150–225 IU for the first days of treatment,[27] but the starting dose of r-hFSH

in the ESPART study will be 300 IU; the higher starting dose of r-hFSH used in the

current study is consistent with the current clinical practice of using increased doses

of gonadotropins in women with a POR.[28]

The ESPART trial was initiated in January 2014. Based on previous analyses, it is

anticipated that the study results will show that a fixed-dose combination of r-hFSH

and r-hLH in a 2:1 ratio during controlled ovarian stimulation is superior to r-hFSH

monotherapy in women with a POR. The clinical importance of the study is

considered to be high, owing to the paucity of well-designed, adequately powered,

multicentre RCTs that have investigated the efficacy and safety of supplemental r-

hLH in women undergoing controlled ovarian stimulation. Furthermore, because the

study uses a POR definition that is aligned with the Bologna criteria, it supports the

aim of the ESHRE to create more homogeneous populations in which new treatment

strategies for POR can be tested and subsequently compared.

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AUTHORS’ CONTRIBUTIONS

PH participated in the conception and design of the study as well as the acquisition of

data. PH will participate in the analysis and interpretation of final data as well as

drafting of and acceptance of the final manuscript. RF participated in the conception

and design of the study and will participate in the analysis and interpretation of the

final data. JS participated in the conception and design of the study and will

participate in the analysis and interpretation of the final data. All authors critically

revised the current work for important intellectual content and gave final approval of

the version of the publication to be published. All authors have agreed to be

accountable for all aspects of the work in ensuring that questions related to the

accuracy or integrity of any part of it are appropriately investigated and resolved.

ACKNOWLEDGEMENTS

The authors would like to thank Amy Evans of inScience Communications, Springer

Healthcare, for providing medical writing support in the preparation of this

manuscript. This support was funded by Merck KGaA Darmstadt.

FUNDING

This study was funded by Merck KGaA Darmstadt.

COMPETING INTERESTS

P. Humaidan and R. Fischer have no competing interests related to this manuscript. J.

Schertz is an employee of EMD Serono Research & Development Institute, Inc..

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REFERENCES

1. European Society of Human Reproduction and Embryology. ART Fact Sheet.

2014. http://www.eshre.eu/Guidelines-and-Legal/ART-fact-sheet.aspx

(accessed 19 December 2014).

2. Practice Committee of American Society for Reproductive Medicine B, Alabama.

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2008;90(5 Suppl):S13-20.

3. Jenkins JM, Davies DW, Devonport H, et al. Comparison of 'poor' responders with

'good' responders using a standard buserelin/human menopausal

gonadotrophin regime for in-vitro fertilization. Hum Reprod 1991;6(7):918-

21.

4. Baruffi RL, Mauri AL, Petersen CG, et al. Recombinant LH supplementation to

recombinant FSH during induced ovarian stimulation in the GnRH-antagonist

protocol: a meta-analysis. Reprod Biomed Online 2007;14(1):14-25.

5. Lehert P, Kolibianakis EM, Venetis CA, et al. Recombinant human follicle-

stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-

hFSH alone for ovarian stimulation during assisted reproductive technology:

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6. Hill MJ, Levens ED, Levy G, et al. The use of recombinant luteinizing hormone in

patients undergoing assisted reproductive techniques with advanced

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7. Oliveira JB, Mauri AL, Petersen CG, et al. Recombinant luteinizing hormone

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Reprod Genet 2007;24(2-3):67-75.

8. Kolibianakis EM, Kalogeropoulou L, Griesinger G, et al. Among patients treated

with FSH and GnRH analogues for in vitro fertilization, is the addition of

recombinant LH associated with the probability of live birth? A systematic

review and meta-analysis. Hum Reprod Update 2007;13(5):445-52.

9. Xiong Y, Bu Z, Dai W, et al. Recombinant luteinizing hormone supplementation in

women undergoing in vitro fertilization/ intracytoplasmic sperm injection with

gonadotropin releasing hormone antagonist protocol: a systematic review and

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10. Legro RS, Kunselman AR. A good meta-analysis is hard to find. Fertil Steril

2012;97(5):1048-9.

11. Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition

of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna


12. Polyzos NP, Devroey P. A systematic review of randomized trials for the

treatment of poor ovarian responders: is there any light at the end of the

tunnel? Fertil Steril 2011;96(5):1058-61 e7.

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13. Ubaldi F, Vaiarelli A, D'Anna R, et al. Management of poor responders in IVF: is

there anything new? Biomed Res Int 2014;2014:352098.

14. Ferraretti AP, Gianaroli L, Motrenko T, et al. LH pretreatment as a novel strategy

for poor responders. Biomed Res Int 2014;2014:926172.

15. Polyzos NP, Blockeel C, Verpoest W, et al. Live birth rates following natural

cycle IVF in women with poor ovarian response according to the Bologna


16. Polyzos NP, De Vos M, Corona R, et al. Addition of highly purified HMG after

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Hum Reprod 2013;28(5):1254-60.

17. Xu B, Li Z, Yue J, et al. Effect of dehydroepiandrosterone administration in

patients with poor ovarian response according to the Bologna criteria. PloS

one 2014;9(6):e99858.

18. Jirge PR, Chougule SM, Gavali VG, et al. Impact of dehydroepiandrosterone on

clinical outcome in poor responders: A pilot study in women undergoing in

vitro fertilization, using bologna criteria. J Hum Reprod Sci 2014;7(3):175-80.

19. Papathanasiou A. Implementing the ESHRE 'poor responder' criteria in research

studies: methodological implications. Hum Reprod 2014;29(9):1835-8.

20. De Placido G, Alviggi C, Perino A, et al. Recombinant human LH

supplementation versus recombinant human FSH (rFSH) step-up protocol

during controlled ovarian stimulation in normogonadotrophic women with

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initial inadequate ovarian response to rFSH. A multicentre, prospective,

randomized controlled trial. Hum Reprod 2005;20(2):390-6.

21. Ruvolo G, Bosco L, Pane A, et al. Lower apoptosis rate in human cumulus cells

after administration of recombinant luteinizing hormone to women undergoing

ovarian stimulation for in vitro fertilization procedures. Fertil Steril

2007;87(3):542-6.

22. Barrenetxea G, Agirregoikoa JA, Jimenez MR, et al. Ovarian response and

pregnancy outcome in poor-responder women: a randomized controlled trial

on the effect of luteinizing hormone supplementation on in vitro fertilization

cycles. Fertil Steril 2008;89(3):546-53.

23. Brunet C, Dechanet C, Reyftmann I, et al. Impact of r-LH supplementation on the

estradiol level during ovarian stimulation for IVF: a randomized prospective

study. Fertil Steril 2009;92(3 (Suppl)):S240.

24. Lisi F, Rinaldi L, Fishel S, et al. Better implantation rate overimposing

recombinant LH (Luveris) on recombinant FSH (Gonal F) in multiple

follicular stimulation for IVF. Hum Reprod 2002;17(Suppl 1):134.

25. Buhler KF, Fischer R. Recombinant human LH supplementation versus

supplementation with urinary hCG-based LH activity during controlled

ovarian stimulation in the long GnRH-agonist protocol: a matched case-

control study. Gynecol Endocrinol 2012;28(5):345-50.

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26. Jeppesen JV, Kristensen SG, Nielsen ME, et al. LH-receptor gene expression in

human granulosa and cumulus cells from antral and preovulatory follicles. J

Clin Endocrinol Metab 2012;97(8):E1524-31.

27. Electronic Medicines Compendium. GONAL-f 450 IU (33 mcg) pen Summary of

Product Characteristics (Merck Serono). 2014.

http://www.medicines.org.uk/emc/medicine/14384 (accessed 17 December

2014).

28. IVF Worldwide. Survey results: poor responders: How to define, diagnose and

treat? Results of 124,700 IVF treatment cycles (196 centres from 45 countries)

(Leong, M. and Patrizio, P.). 2010. http://www.ivf-worldwide.com/news/276-

newsletter-august-82010.html (accessed 17 December 2014).

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1______

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______3______

2b All items from the World Health Organization Trial Registration Data Set ______3______

Protocol version 3 Date and version identifier ______3______

Funding 4 Sources and types of financial, material, and other support ______16_____

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ______1______

5b Name and contact information for the trial sponsor ______1______

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

____16_______

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

_Not included____

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Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

______4-5____

6b Explanation for choice of comparators _____4-5_____

Objectives 7 Specific objectives or hypotheses ____5, 10_____

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

_____5-6_____

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

6 (countries not

specified)

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

_____6-7_____

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

_____7-8_____

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

____8-9______

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

_____8_______

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ______8______

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

____10-11____

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

____7-10_____

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

____10-11____

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _____3_______

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

_____9_______

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

_____9_______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

_____9_______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

_____9_______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

__Not included__

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

___Not included__

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

___Not included__

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

___Not included__

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

____11_______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____11______

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

_____11______

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

___Not included__

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

__Not included___

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

____10_______

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

_ Not included

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ____2-3______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

____2-3______

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5

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

____3, 6_____

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

___Not included__

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

___Not included__

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site ____16_______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

___Not included__

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

__Not included___

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

___Not included__

31b Authorship eligibility guidelines and any intended use of professional writers ____16_______

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code __Not included___

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates __Not included__

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

__Not included___

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2–4

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 5–7

2b Specific objectives or hypotheses 7

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 7 and 9

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons N/A

Participants 4a Eligibility criteria for participants 8–9

4b Settings and locations where the data were collected 7

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

9–10

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

11

6b Any changes to trial outcomes after the trial commenced, with reasons N/A

Sample size 7a How sample size was determined 12

7b When applicable, explanation of any interim analyses and stopping guidelines N/A

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 11

8b Type of randomisation; details of any restriction (such as blocking and block size) 11

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned TBC

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions TBC

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 11

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assessing outcomes) and how

11b If relevant, description of the similarity of interventions N/A

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 12

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses N/A

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

N/A

13b For each group, losses and exclusions after randomisation, together with reasons N/A

Recruitment 14a Dates defining the periods of recruitment and follow-up N/A

14b Why the trial ended or was stopped N/A

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group N/A

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

N/A

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

N/A

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended N/A

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

N/A

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) N/A

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 15

Generalisability 21 Generalisability (external validity, applicability) of the trial findings N/A

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence N/A

Other information

Registration 23 Registration number and name of trial registry 7

Protocol 24 Where the full trial protocol can be accessed, if available

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 17

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

Comment [Anon1]: A complete protocol will not be publically available as it is deemed to be proprietary information. A protocol synopsis in the form of this publication and as posted on ClinicalTrials.gov is deemed sufficient.

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