Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study

Abstract

Background:

Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy.

Objective:

To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo.

Methods:

POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo.

Results:

Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58–1.39), placebo = 0.97 (0.63–1.50) (p = 0.79)).

Conclusion:

POPARTMUS failed showing efficacy of a NOMAc–E2 combination in preventing post-partum relapses.

Keywords

Multiple sclerosis relapses post-partum sex hormones estradiol progesterone

There is strong evidence that pregnancy influences the course of multiple sclerosis (MS). The rate of relapses is reduced during the last 3 months of pregnancy and increased in the post-partum period.^1,2

Several hormones increase during pregnancy and could explain these dramatic changes. Sex steroids are currently the most attractive candidates. Estriol (E3) was shown to improve MS while inducing an increase in anti-inflammatory IL10 levels (Th2) and a decrease in proinflammatory TNF-α (Th1).^3,4 Progesterone may also have an effect by inducing a shift in the Th1/Th2 balance towards Th2 anti-inflammatory responses.⁵

Currently available disease-modifying treatments (DMTs) are usually stopped for pregnancy, and none of them, except maybe natalizumab,⁶ can rapidly prevent the post-partum rebound. There is only low-level evidence supporting the use of intravenous immunoglobulins^7,8 or methylprednisolone for preventing post-partum relapses.⁹

We hypothesized that a progestogen structurally derived from 19-nor progesterone administered after delivery could prevent post-partum relapses. Our objective was to compare MS activity in the post-partum, in women treated immediately after delivery and for 3 months with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2), or placebo.

Methods

Study design

POPARTMUS was a multicenter, randomized, 12-week placebo-controlled, double-blinded, proof-of-concept trial, conducted in France and Italy (Supplementary data, protocol and Figure S1). The study protocol was approved by a central ethics committee for France and by local ones in Italy. It was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonization and good clinical practice guidelines. All women provided written informed consent. POPARTMUS is registered in clinicaltrials.gov (NCT00127075).

Participants

Eligible patients were pregnant women (36 weeks or less of amenorrhea), aged ⩾18 years, with a diagnosis of MS according to MacDonald’s 2001 criteria,¹⁰ a relapsing–remitting (RR) or secondary progressive (SP) course and an Expanded Disability Status Scale (EDSS) score ⩽6.0. Participants were ineligible if they had a Clinically Isolated Syndrome not fulfilling MacDonald’s criteria, primary progressive MS, ongoing or previous myocardial infarction, stroke or venous thrombo-embolism, breast or uterine cancer, severe liver disorder, undiagnosed genital bleeding and hypersensitivity to one of the study treatments. More specifically, women were excluded if they were willing to breastfeed, start a DMT in the 24 weeks after delivery or refused a non-hormonal contraception in the 12 weeks following delivery.

Procedure

Patients received either NOMAc, one tablet of 5 mg daily during the first 2 weeks post-partum and two tablets (10 mg daily) simultaneously over the next 10 weeks, together with transdermal 17-beta-estradiol, 75 µg weekly since day 15, or identical placebo tablets and patches.

Outcomes

The primary outcome was the annualized relapse rate (ARR) in the first 12 weeks after delivery. Secondary clinical and magnetic resonance imaging (MRI) outcomes are detailed in the Supplementary material.

Statistical analysis

The intention to treat population was defined as women who had at least 1 day of follow-up and who did not present any exclusion criteria before the beginning of the treatment (N = 192). A Poisson’s regression model was used to compare the ARR, using a likelihood-ratio test to test the treatment effect. A two-sided p-value of less than 0.05 was considered for rejecting the null hypothesis.

The sample size calculation was based on the Pregnancy in Multiple Sclerosis (PRIMS) study; we expected an ARR in the placebo group of 1.2, and, if the treatment was effective, a decrease to 0.8. With a type 1 error of 5% and a power of 90%, 131 patients per group were required; therefore, the sample size was fixed to 300 patients.

Results

From June 2005 to October 2011, 202 patients were included in the study and randomly assigned to receive NOMAc and 17-beta-estradiol (n = 102) or placebo (n = 100). Due to a slow rate of inclusions, the steering committee decided to stop the study after 200 patients were included.

Demographic and baseline characteristics were comparable across groups (Table 1). The study flow chart is presented in the Supplementary data (Figure S2).

Table 1.

Demographics and baseline disease characteristics.

	Placebo (n = 100)	Sexual steroids (n = 102)
Age at MS onset – years	n = 97	n = 101
Mean ± SD	25.1 ± 5.7	24.4 ± 4.4
Range	14–40	10–35
Age at inclusion – years	n = 97	n = 101
Mean ± SD	32.1 ± 5.1	31.8 ± 4.3
Range	18.3–46.0	23.9–42.3
Clinical course – n (%)	n = 97	n = 101
Clinically isolated syndrome	8 (8.2%)	10 (10%)
Fulfilling MacDonald’s criteria for MS	8 (8.2%)	10 (10%)
Relapsing–remitting MS	86 (88.7%)	91 (90%)
Secondary progressive MS	3 (3.1%)	0
Number of previous pregnancies	n = 94	n = 101
Mean ± SD	0.65 ± 0.67	0.62 ± 0.77
0	43 (45.7%)	54 (53.5%)
1	41 (43.7%)	33 (32.7%)
2	10 (10.6%)	12 (11.8%)
3	0	2 (2%)
Annualized relapse rate	n = 90	n = 98
Mean (95% confidence interval)
In the year before pregnancy	0.72 (0.57–0.91)	0.55 (0.43–0.72)
During pregnancy	0.40 (0.28–0.57)	0.28 (0.18–0.43)
Total number of previous relapses	n = 90	n = 98
Mean ± SD	5.11 ± 4.0	4.60 ± 3.3
Range	1–20	1–15
Time since the last relapse – months	n = 90	n = 98
Mean ± SD	18.3 ± 20.1	19.3 ± 19.1
DSS at inclusion	n = 94	n = 95
Mean ± SD	1.37 ± 1.5	1.19 ± 1.3
Range	0–7	0–6
Previous DMT	n = 100	n = 102
No treatment	29 (29%)	30 (29.4%)
Moderately active	64 (64%)	59 (57.8%)
Highly active	1 (1%)	9 (8.8%)
Missing	6 (6%)	4 (3.9%)
Time since DMT cessation – months	n = 54	n = 60
Mean ± SD	8.7 ± 10.7	7.9 ± 7.8
Range	0.1–56.2	0.1–32.7
Moderately active	5.3 ± 11.0	5.6 ± 7.7
Highly active	2.6*	10.0 ± 9.3

MS: multiple sclerosis; SD: standard deviation; DMT: disease-modifying treatment; DSS: disability status scale.

Sexual steroids are oral nomegestrol acetate and 17-beta-oestradiol; moderately active DMTs are interferons beta (91), glatiramer acetate (26), azathioprine (2), dimethyl fumarate (trial, 1) and firategrast (trial, 1); highly active DMTs are natalizumab (6), mitoxantrone (2) and cyclophosphamide (2).

SD is not assessable (one case only).

POPARTMUS did not meet the primary endpoint at week 12. The ARR was 0.90 (0.58–1.39) in the sex steroid group compared to 0.97 (0.63–1.50) in the placebo group (p = 0.79) (Figure 1). None of the other clinical or MRI outcomes was significant (Table S1).

Ten serious adverse events were reported, four on placebo and six in the sex steroid group. Six could be related to pregnancy and delivery, and two were directly related to MS (Table S2).

Discussion

The POPARTMUS study failed at showing efficacy of a NOMAc–E2 combination on preventing post-partum relapses in MS and no differences could be shown regarding secondary clinical and MRI outcomes. The hypothesis raised here had to be addressed through an investigator initiated randomized trial, since the expected market for such drugs would be very narrow. As most of investigator-initiated trials, POPARTMUS faced several difficulties linked to a low level of funding. Drug management was performed by a clinical research organization (CRO), but sponsorship, data management and investigator monitoring had to be performed only by highly motivated clinicians in addition to their daily work. All these facets of the trial could, however, be managed, but the study suffered from a too slow inclusion rate, for various reasons, including the exclusion of women willing to breastfeed, due to the transfer of sex hormones into the breast milk. The early termination led to decrease the study power. In addition, the original sample size calculation was based on annualized relapse rates whereas the duration of follow-up was only 3 months. The correct sample size to ensure a power of 90% was therefore greater than 300. Anyway, the absolute difference of ARR observed at week 12 (0.97 vs 0.90) was negligible and had no clinically significance. One could argue that blinding was limited because the neurologist rating relapses were following the patient and aware of the relapses and adverse events. This could unlikely have introduced a bias, as it is usually favouring the active treatment. Baseline characteristics revealed a trend towards a lower disease activity in the pre-pregnancy year and during pregnancy in the sex steroid group. The primary outcome being negative, we decided not to perform unplanned post hoc sensitivity analyses to adjust for those criteria, as this would not have reversed the conclusion of the study. The main issue was probably the choice and most of all the doses of active hormone that was arbitrarily chosen without any previous dose-finding approach. In POPARTMUS, NOMAc was given at high doses leading to a plasma concentration in the aim to mimic high doses of progesterone reached during pregnancy. The intake of 3.75 mg NOMAc daily by pre-menopausal women results in a plasma concentration of 7.21 ng/mL; a plasmatic concentration of 22 ng/mL can be expected under 10 mg. This concentration is less than that of progesterone during the third trimester of pregnancy (100–160 ng/mL), but NOMAc has a high progestational potency. Finally, the duration of the study was short and an effect may need longer to appear.

In conclusion, the POPARTMUS study failed in demonstrating a reduction of post-partum relapses in women with MS using a combination of NOMAc and 17-beta-estradiol. The sex hormone track deserves, however, to be further explored in the future.

Supplemental Material

sj-pdf-1-msj-10.1177_1352458520978218 – Supplemental material for Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study

Supplemental material, sj-pdf-1-msj-10.1177_1352458520978218 for Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study by Sandra Vukusic, Iuliana Ionescu, Catherine Cornu, Nadine Bossard, Françoise Durand-Dubief, François Cotton, Luca Durelli, Romain Marignier, Laurence Gignoux, David-Axel Laplaud, Thibault Moreau, Pierre Clavelou, Jérôme De Seze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Maria Trojano, Francesco Patti, Etienne-Emile Baulieu, Laurent Remontet and Martine El-Etr in Multiple Sclerosis Journal

Supplemental Material

sj-pdf-2-msj-10.1177_1352458520978218 – Supplemental material for Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study

Supplemental material, sj-pdf-2-msj-10.1177_1352458520978218 for Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study by Sandra Vukusic, Iuliana Ionescu, Catherine Cornu, Nadine Bossard, Françoise Durand-Dubief, François Cotton, Luca Durelli, Romain Marignier, Laurence Gignoux, David-Axel Laplaud, Thibault Moreau, Pierre Clavelou, Jérôme De Seze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Maria Trojano, Francesco Patti, Etienne-Emile Baulieu, Laurent Remontet and Martine El-Etr in Multiple Sclerosis Journal

Footnotes

Acknowledgements

The authors like to thank Rottapharm that provided 17-beta-estradiol patches (especially Claudio Benvenutti).

Author contributions

S.V. and I.I. contributed to the study concept and design, acquisition of data, analysis and interpretation, and writing. C.C. and N.B. contributed to the study concept and design, analysis and interpretation, and writing. F.D.-D., F.C. and L.D. contributed to the study concept and design, acquisition of data and critical revision of the manuscript for important intellectual content. R.M. and L.G. contributed to the acquisition of data, analysis and interpretation, and critical revision of the manuscript for important intellectual content. D.-A.L., T.M., P.C., J.D.S., M.D., D.B., J.P., C.L.-F., E.L.P., G.C., E.B., P.H., O.H., M.T. and F.P. contributed to the acquisition of data and critical revision of the manuscript for important intellectual content. E.-E.B. contributed to the study concept and design, and critical revision of the manuscript for important intellectual content. L.R. contributed to the study concept and design, analysis and interpretation, and writing. M.E.-E. contributed to the study concept and design, acquisition of data, analysis and interpretation, and writing.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: S.V. has received grants, personal fees and non-financial support from Biogen; personal fees from Celgene; grants, personal fees and non-financial support from Genzyme; grants and personal fees from MedDay; grants, personal fees and non-financial support from Merck Serono; grants, personal fees and non-financial support from Novartis; grants, personal fees and non-financial support from Roche; grants, personal fees and non-financial support from Sanofi; personal fees from Teva, all outside the submitted work. I.I., C.C., N.B., F.D.-D., F.C. and L.D. have nothing to disclose in relation with this study. R.M. serves on scientific advisory boards for MedImmune and Viela Bio; and has received funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva, and Viela Bio. L.G. has nothing to disclose. D.-A.L. has received grants, personal fees and non-financial support from Biogen; grants, personal fees and non-financial support from Genzyme; grants and personal fees from MedDay; grants, personal fees and non-financial support from Merck Serono; grants, personal fees and non-financial support from Novartis; grants, personal fees and non-financial support from Roche; grants, personal fees and non-financial support from Sanofi; personal fees from Teva, all outside the submitted work. T.M. has received consulting and lecturing fees, travel grants and research support from Biogen, Genzyme, Novartis, MedDay, Merck Serono, Roche, Sanofi Aventis and Teva Pharma. P.C., J.D.S., M.D. and D.B. have nothing to disclose in relation with this study. J.P. has received consulting and lecturing fees, travel grants and unconditional research support from Biogen, Genzyme, Novartis, MedDay, Merck Serono, Roche, Sanofi Aventis and Teva Pharma. C.L.-F. has received lecturing fees from Roche and Genzyme. E.L.P., G.C., E.B. and P.H. have nothing to disclose in relation with this study. O.H. has received personal fees and non-financial support from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, Biogen; grants from Roche, Merck, Novartis and Biogen. M.T., F.P., E.-E.B., L.R. and M.E.-E. have nothing to disclose in relation with this study.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work has been supported by unrestricted grants from patient’s associations: Fondation pour l’Aide à la Recherche sur la Sclérose en Plaques (ARSEP Foundation), the Myelin Project and the European Leukodystrophy Association (ELA) and Foundation, and from the French Ministry of Health: Programme Hospitalier de Recherche Clinique – National call for proposal.

Steering committee

Dr Iuliana Ionescu, Professor Christian Confavreux, Professor Sandra Vukusic (Lyon, France), Dr Catherine Cornu (Lyon, France) and Dr Martine El.-Etr (Kremlin-Bicêtre, France).

Protocol design committee

Professor Etienne-Emile Baulieu., Dr Martine El-Etr, Dr Michel Schumacher (Kremlin-Bicêtre, France), Dr Iuliana Ionescu, Professor Christian Confavreux, Professor Sandra Vukusic (Lyon, France) and Dr Catherine Cornu (Lyon, France).

Advisors

Professor Hans-Peter Hartung (Dusseldorf, Germany), Professor David H. Miller (London, UK), Dr Michael Hutchinson (Dublin, Ireland), Professor Michel Pugeat (Lyon, France), Dr Catherine d’Archangues (Genève, CH), Dr Jacqueline Conard (Paris, France), Professor Joël Ménard (Paris, France) and Dr Régine Sitruk-Ware (New York, USA).

Gynaecologists committee

Dr Clara Pelissier (Paris, France), Dr Suzanne Dat (Toulouse, France), Dr Joëlle Belaïsch-Allard (Sèvres, France), Dr Nicole Athéa (Paris, France) and Dr Dominique Büschsenschutz (Paris, France).

Data monitoring committee

Professor Olivier Lyon-Caen (Paris, France), Dr Richard Gonsette (Melsbroek, Belgium), Professor Jean-Pierre Boissel (Lyon, France) and Dr Patrick Ffrench (Lyon, France).

MRI committee

Dr Françoise Durand-Dubief (Lyon, France), Professor François Cotton (Lyon, France), Mr Chahin Pachai and Mr Luc Bracoud (Bioclinica, Lyon, France).

The authors are indebted to the patients for their participation to the POPARTMUS study.

POPARTMUS investigators

France (179) Lyon (25): Sandra VUKUSIC, Iuliana IONESCU, Géraldine ANDRODIAS, Romain MARIGNIER, Guy CHAUPLANNAZ; Nantes (16): David LAPLAUD, Sandrine WIERTLEWSKI, Caroline LANCTIN-GARCIA; Dijon (14): Thibault MOREAU, Grégory COUVREUR, Guillaume MADINIER; Clermont-Ferrand (13): Pierre CLAVELOU, Frédéric TAITHE, Dominique AUFAUVRE, Nathalie GUY, Ana FERRIER; Strasbourg (13): Jérôme DE SEZE, Nicolas COLLONGUES; Nancy (11): Marc DEBOUVERIE; Toulouse (11): Frédérique VIALA, David BRASSAT, Angélique GERDELAT-MAS, Patrice HENRY; Marseille (10): Jean PELLETIER, Audrey RICO-LAMY; Nice (9): Christine LEBRUN-FRENAY; Rennes (9): Emmanuelle LE PAGE, Véronique DEBURGHRAEVE, Gilles EDAN; Nîmes (7): Giovanni CASTELNOVO; Besançon (5): Eric BERGER; Lille (4): Patrick HAUTECOEUR, Maxime BLONDIAUX; Poissy (4): Olivier HEINZLEF; Quimper (3): Marc COUSTANS; Montbeliard (2): Christine CLERC; Chamalières (2): Laurent RIEU, Michel LAUXEROIS; Saint Herblain (2): Grégoire HINZELIN; Bordeaux (2): Jean-Christophe OUALLET; Chalon sur Saône (2): Dominique MINIER, Philippe VION; Montélimar (2): Nathalie GROMAIRE-FAYOLLE; Caen (2): Nathalie DERACHE; Montpellier (2): Eric THOUVENOT; Paris Val de Grâce (1): Magali SALLANSONNET-FROMENT; Avignon (1): Patricia TOURNIAIRE; Annemasse (1): Laure TOUREILLE; Grenoble (1): Florent BORGEL; Paris Salpêrière (1): Bruno STANKOFF; Chartres (1): Jérôme GRIMAUD; Belfort (1): Coralia MOROIANU; Tours (1): Anne-Marie GUENNOC; Chambéry (1): Claire-Lise TOURNIER-GERVASON; Villefranche (1): Stéphane PEYSSON.

Italy (23) Bari (6): Maria TROJANO; Catania (5): Francesco PATTI, Emanuele D’AMICO; Reggio Emilia (5): Luisa MOTTI; Gallarate (4): Mauro ZAFFARONI; Orbassano (3): Luca DURELLI, Alessia TAVELLA.

ORCID iDs

Sandra Vukusic

François Cotton

Francesco Patti

Supplemental material

Supplemental material for this article is available online.

References

Confavreux

Hutchinson

Hours

, et al. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339: 285–291.

Vukusic

Marignier

Multiple sclerosis and pregnancy in the ‘treatment era’. Nat Rev Neurol 2015; 11(5): 280–289.

Sicotte

Liva

Rochelle

, et al. Treatment of multiple sclerosis with pregnancy hormone Estriol. Ann Neurol 2002; 52: 421–428.

Soldan

AlvarezRetuerto

Sicotte

, et al. Immune modulation in multiple sclerosis patients treated with pregnancy hormone estriol. J Immunol 2003; 171: 6267–6274.

Szekeres-Bartho

Halasz

Palkovics

Progesterone in pregnancy; receptor–ligand interaction and signaling pathways. J Reprod Immunol 2009; 83(1-2): 60–64.

Vukusic

Durand-Dubief

Benoit

, et al. Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis. Mult Scler 2015; 21(7): 953–955.

Achiron

Kishner

Dolev

, et al. Effect of intravenous immunoglobulin treatment on pregnancy and post-partum related relapses in multiple sclerosis. J Neurol 2004; 251: 1133–1137.

Haas

Hommes

OR.

A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007; 13(7): 900–908.

de Seze

Chapelotte

Delalande

, et al. Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult Scler 2004; 10(5): 596–597.

10.

McDonald

Compston

Edan

, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50(1): 121–127.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.12 MB

0.23 MB