Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.

STUDY QUESTION: Does a single oral dose of nolasiban 900 mg administered 4 h before embryo transfer (ET) increase pregnancy rates in women undergoing IVF? SUMMARY ANSWER: In an individual patient data (IPD) meta-analysis of three clinical trials, a single oral dose of nolasiban 900 mg was associated with an increased ongoing pregnancy rate of an absolute 5% (relative 15%). WHAT IS KNOWN ALREADY: Several clinical studies have shown that blocking activation of oxytocin receptors by an oxytocin receptor (OTR) antagonist has the potential to decrease uterine contractions, increase endometrial perfusion and enhance endometrial decidualisation and other parameters of endometrial receptivity. It has been hypothesised that antagonism of oxytocin receptors could improve the likelihood of successful embryo implantation and thus increase pregnancy and live birth rates following ET. STUDY DESIGN, SIZE, DURATION: This is an analysis of three randomised, double-blind, placebo-controlled trials, which randomised 1836 subjects between 2015 and 2019. We describe the results of a meta-analysis of individual participant data (IPD) from all three trials and the pre-specified analyses of each individual trial. PARTICIPANT/MATERIAL, SETTING, METHODS: Participants were patients undergoing ET following IVF/ICSI in 60 fertility centres in 11 European countries. Study subjects were below 38 years old and had no more than one previously failed cycle. They were randomised to a single oral dose of nolasiban 900 mg (n = 846) or placebo (n = 864). In IMPLANT 1, additional participants were also randomised to nolasiban 100 mg (n = 62) or 300 mg (n = 60). Fresh ET of one good quality embryo (except in IMPLANT 1 where transfer of two embryos was allowed) was performed on Day 3 or Day 5 after oocyte retrieval, approximately 4 h after receiving the study treatment. Serum hCG levels were collected at 14 days post oocyte retrieval (Week 2) and for women with a positive hCG result, ultrasound was performed at Week 6 post-ET (clinical pregnancy) and at Week 10 post-ET (ongoing pregnancy). Pregnant patients were followed for maternal (adverse events), obstetric (live birth, gestational age at delivery, type of delivery, incidence of twins) and neonatal (sex, weight, height, head circumference, Apgar scores, congenital anomalies, breast feeding, admission to intensive care and specific morbidities e.g. jaundice, respiratory distress syndrome) outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: In an IPD meta-analysis of the clinical trials, a single oral dose of nolasiban 900 mg was associated with an absolute increase of 5.0% (95% CI 0.5, 9.6) in ongoing pregnancy rate and a corresponding increase of 4.4% (95% CI -0.10, 8.93) in live birth rate compared to placebo. Similar magnitude increases were observed for D3 or D5 transfers but were not significantly different from the placebo. Population pharmacokinetics (PK) demonstrated a correlation between higher exposures and pregnancy. LIMITATIONS, REASON FOR CAUTION: The meta-analysis was not a pre-specified analysis. While the individual trials did not show a consistent significant effect, they were not powered based on an absolute increase of 5% in ongoing pregnancy rate. Only a single dose of up to 900 mg nolasiban was administered in the clinical trials; higher doses or extended regimens have not been tested. Only fresh ET has been assessed in the clinical trials to date. WIDER IMPLICATIONS OF THE FINDINGS: The finding support the hypothesis that oxytocin receptor antagonism at the time of ET can increase pregnancy rates following IVF. The overall clinical and population PK data support future evaluation of higher doses and/or alternate regimens of nolasiban in women undergoing ET following IVF. STUDY FUNDING/COMPETING INTERESTS: The trials were designed, conducted and funded by ObsEva SA. A.H., O.P., E.G., E.L. are employees and stockholders of ObsEva SA. E.L. is a board member of ObsEva SA. G.G. reports honoraria and/or non-financial support from ObsEva, Merck, MSD, Ferring, Abbott, Gedeon-Richter, Theramex, Guerbet, Finox, Biosilu, Preglem and ReprodWissen GmbH. C.B. reports grants and honoraria from ObsEva, Ferring, Abbott, Gedeon Richter and MSD. P.P. reports consulting fees from ObsEva. H.T. reports grants and or fees from ObsEva, Research Fund of Flanders, Cook, MSD, Roche, Gedeon Richter, Abbott, Theramex and Ferring. H.V. reports grants from ObsEva and non-financial support from Ferring. P.T. is an employee of Cytel Inc., who provides statistical services to ObsEva. J.D. reports consulting fees and other payments from ObsEva and, Scientific Advisory Board membership of ObsEva. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02310802, NCT03081208, NCT03758885. TRIAL REGISTRATION DATES: December 2014 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885). FIRST PATIENT'S ENROLMENT: January 2015 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885).

Effect of altered serum lipid concentrations on the IC50 of halofantrine against Plasmodium falciparum.

Halofantrine (Hf) is a highly lipophilic antimalarial which significantly associates with triglyceride (TG) rich plasma lipoproteins, and this is likely manifest as a decrease in the free fraction of drug. This study assessed the effect of using growth media containing 10% serum containing different concentrations of TG (i.e. TG-rich plasma lipoproteins) on the IC50 of Hf determined using continuous in vitro culture of Plasmodium falciparum. Serum was collected from a human subject in either a fasted state or at various times after ingestion of a fatty meal. There was a linear and statistically significant 2.5-fold increase in the IC50 of Hf across a 6-fold range of increasing TG concentrations, with the increased IC50 values being ascribed to a decreased free fraction of Hf in the growth media due to sequestration by TG-rich lipoproteins. Chloroquine diphosphate, which is hydrophilic and not significantly bound by TG-rich lipoproteins, was used as a control and its IC50 values were independent of TG concentrations. These data indicate that consideration should be given to the adoption of standard conditions for the collection of serum with respect to pre- or postprandial states, and that subject- and disease-related factors which alter plasma lipoprotein profiles should be considered when interpreting the IC50 profile of Hf (and possibly other lipophilic antimalarials). Furthermore, although food is known to affect the pharmacokinetics of Hf, these data suggest that altered plasma lipoprotein profiles could also influence its pharmacodynamic profile.

A physicochemical basis for the effect of food on the absolute oral bioavailability of halofantrine.

Halofantrine hydrochloride (Hf.HCl) is a highly lipophilic phenanthrenemethanol antimalarial. The poor and erratic absorption of Hf after oral administration has been implicated in some treatment failures. Food increases the oral bioavailability of Hf in humans approximately 3-5-fold, although neither the absolute bioavailability nor the basis for the food effect has been fully defined. In this study, the mean (+/-SD, n = 3) absolute oral bioavailability of 250 mg Hf.HCl tablets in beagles was 8.6 +/- 5.3% in the fasted state, which increased approximately 12-fold when administered postprandially. These data indicate that Hf.HCl is efficiently absorbed from the postprandial intestinal environment. The solubility and intrinsic dissolution rate of Hf.HCl were investigated as a function of bile salt concentration (sodium taurocholate, NaTC, 0-30 mM) and micellar composition (4:1 NaTC:lecithin). At premicellar (fasted) concentrations of NaTC (< 5 mM), the solubility and intrinsic dissolution rate were very low (< 15 micrograms/mL; < 0.01 microgram s-1 cm-2). At NaTC concentrations typical of the postprandial state, the solubility and dissolution rate improved dramatically. For example, solubility in 30 mM NaTC increased approximately 1000-fold relative to buffer control, with even greater enhancement (3000-fold) associated with mixed micellar systems. These data suggest that the improved absorption of Hf.HCl in the fed state is most likely due to the increased solubilization and dissolution of the drug in the presence of bile salt mixed micelles.

Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion.

The intestinal lymphatic transport of halofantrine, an important, highly lipophilic antimalarial drug, has been studied in a conscious rat model after oral administration. In these studies, the lymphatic transport of Hf free base when coadministered with lipid was approximately 20% of the administered dose compared with 5% transport after administration of the HCl salt with or without lipid. These differences in transport can be attributed to the increased lipophilicity of the free base (relative to the HCl salt) thereby facilitating greater association of Hf base with the products of luminal lipid digestion and the subsequent interaction with the intestinally derived chylomicrons responsible for lymphatic drug transport. In contrast to previous results in an anesthetized rat model where lymphatic transport was dependent on the characteristics of the intraduodenally administered lipid formulations, the lymphatic transport of Hf base in the conscious rat was independent of both the class of administered lipid (triglyceride or fatty acid) and the extent of formulation dispersion (micellar lipid or lipid solution). Considering the different lymphatic transport profiles of Hf base in the anesthetized and conscious rat models, it is proposed that the lipid vehicle effects observed in the intraduodenally dosed anesthetized model most likely reflects the lack of gastric processing by preduodenal lipase and the shear action of the stomach otherwise present in the conscious rat model.

Association of halofantrine with postprandially derived plasma lipoproteins decreases its clearance relative to administration in the fasted state.

The oral bioavailability of halofantrine (Hf), a highly lipophilic phenanthrenemethanol antimalarial, is significantly enhanced when ingested with food. Although food enhances the absorption of Hf, it also alters the intrinsic pharmacokinetics of Hf as the observed postprandial absolute bioavailability was greater than 100% (Humberstone et al., J. Pharm. Sci. 1996, 85, 525-529). In this study, the association of Hf with plasma lipoproteins and the effect of postprandial lipoproteins on the pharmacokinetics of Hf after intravenous administration was examined in beagles. In fasted dogs, approximately 50% of plasma Hf was associated with lipoproteins, with HDL accounting for 42-43%, LDL for 4-5%, and triglyceride rich lipoproteins (TRL) for 2-3%. At 0.5 and 2 h postdosing in the postprandial state, the proportion of Hf present in both TRL and LDL increased to 7-10%. Changes in Hf distribution between lipoprotein fractions reflected the respective postprandial changes in plasma triglyceride (TG) concentrations. In terms of pharmacokinetics, when an equivalent dose of Hf was administered intravenously in a crossover study to fed and fasted beagles, plasma Hf AUC values were significantly higher, and CL and Vss were significantly lower, in the fed state compared to the fasted state (p < 0.05). The mean postprandial increase in plasma AUC values was 19% (range 14-34%), with corresponding decreases in CL (15%) and Vss (21%). A broadly linear relationship between increased postprandial Hf concentrations at specific time points (fed vs fasted) and corresponding postprandial increases in TG concentrations suggested that the decreased postprandial clearance of Hf was a function of increased association with TG-rich plasma lipoproteins. This study confirms that the clearance of Hf is influenced by plasma lipoprotein profiles, and the findings have implications for the design and interpretation of fed/fasted bioavailability studies of lipophilic drugs and determination of their intrinsic pharmacokinetic parameters in subjects or patients with dyslipidemic profiles.

A simplified liquid chromatography assay for the quantitation of halofantrine and desbutylhalofantrine in plasma and identification of a degradation product of desbutylhalofantrine formed under alkaline conditions.

The development of a new and simplified, validated LC assay for the quantitation of halofantrine and desbutylhalofantrine in plasma is described. The methodology employs an inexpensive, rapid and simple liquid-liquid extraction procedure in combination with previously reported chromatographic conditions. The method has been employed to study aspects of the pharmacokinetics of orally administered halofantrine in beagle dogs and some preliminary data are presented. During development of the extraction procedure, degradation of desbutylhalofantrine was observed under non-acidic conditions in the extraction solvent (tert-butyl methyl ether) and we also report the structural elucidation of the breakdown product and the conditions required to avoid this degradation.

The Blo-Bag, a disposable spacer.

" Blo -Bag", a new disposable spacer device, has been tested in conjunction with Duovent metered dose inhaler. Duovent produced a significant bronchodilatation for the duration of the study. When delivered by the " Blo -Bag" it produced a significantly greater increase in peak expiratory flow rate than when delivered by metered dose inhaler. There were no significant side effects.

Fenoterol plus ipratropium ('Duovent') aerosol therapy delivered by a tube spacer.

A randomized crossover study was carried out in 12 patients with reversible airflow obstruction to investigate the bronchodilator effects of a single metered dose of fenoterol hydrobromide (200 micrograms) plus ipratropium bromide (80 micrograms) delivered by the standard aerosol inhaler or by the inhaler with an extension tube spacer. The results of lung function tests showed that there were significant increases from baseline values in FEV1, FVC and PEFR by 15 minutes using both drug delivery methods, and the improvement in PEFR was maintained for at least 8 hours in 11 of the 12 patients. Although no significant differences in the results was demonstrated between the two methods, which were used correctly by all the participants, it is suggested that the spacer device method would be particularly useful for patients who have difficulty in co-ordinating drug delivery with inhalation.

Pulmonary arterial hypertension and emphysema.

Pulmonary artery pressures were estimated by an indirect method using echocardiography (Boyd et al. 1980), in a group of patients with chronic airflow obstruction, in order to investigate the degree of pulmonary hypertension in patients with emphysema. We found a positive correlation between the estimated pulmonary artery end diastolic pressure (PAEDP) and the radiological emphysema score (r = 0.58, P less than 0.005), and between the estimated PAEDP and the transfer constant for carbon monoxide (KCO) (r = 0.66, P less than 0.002). There was no correlation between the PAEDP and the arterial partial pressure of oxygen (PaO2) before exercise, between the PAEDP and the change in oxygen partial pressure after exercise, or between the KCO and the PaO2. It is suggested that emphysema does predispose to pulmonary arterial hypertension and that the relationship is probably secondary to vessel destruction rather than hypoxia.

Laser therapy in 100 tracheobronchial tumours.

One hundred patients with tracheobronchial tumours were treated with the neodymium YAG (yttrium-aluminium-garnet) or argon laser for symptoms of airways obstruction caused by tumour (59 cases), complete collapse of a lung (17 cases), or recurrent haemoptysis (24 cases). Seventy four of them had relapsed or failed to respond to radiotherapy or chemotherapy and all were inoperable. Objective improvement in results of lung function tests or haemoptysis diary charts was seen in 37 patients with airways obstruction (63%), five (29%) with collapsed lung, and 14 (58%) with haemoptysis. Overall, 68 patients had symptomatic benefit and there was objective improvement in 56. Two deaths occurred in 288 treatment sessions both occurring as a result of asphyxia from minor haemorrhage in patients with advanced cylindromas and critical narrowing of the trachea or single remaining bronchus. In suitable patients with intraluminal tumour laser phototherapy is a valuable addition to conventional treatment.