Removal of a well-palpable one-rod subdermal contraceptive implant using a dedicated hand-held device or standard technique: a randomized, open-label, non-inferiority trial.

STUDY QUESTION: Is a mechanical hand-held device for removing a single-rod subdermal contraceptive implant safe for implant users? SUMMARY ANSWER: In terms of safety, the device is non-inferior to the standard technique for implant removal. WHAT IS KNOWN ALREADY: An easy-to-use device for removing a subdermal contraceptive implant may be helpful in settings where skilled providers are in short supply. Prior to this study, the only report on the world's first hand-held, mechanical device with build-in incisor was a Swedish study using earlier versions of the product. STUDY DESIGN, SIZE, DURATION: From December 2019 to November 2020, we conducted a three-arm, open-label non-inferiority randomized trial involving 225 Ugandan women to assess safety (primary outcome) and measure implant removal efficacy (secondary outcomes) of a newly developed, hand-held device, compared to the standard removal technique. PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized participants desiring removal of their one-rod contraceptive implant in a 1:1:1 ratio: standard technique/lidocaine injection, new device/lidocaine patch or new device/lidocaine injection. For primary safety endpoints, we examined removal complications and grouped them according to severity. For secondary endpoints on efficacy, we defined three device outcomes: intact implant removed without additional tools (primary), implant removed allowing implant breakage, but without tools (secondary) and implant removed allowing implant breakage and non-scalpel tools (tertiary). We assessed provider feedback on the device and used chi-square tests for all comparisons. MAIN RESULTS AND THE ROLE OF CHANCE: We recruited 225 participants and randomly assigned (n = 75) to each group. For safety, no primary complications occurred in any treatment group, while only one secondary complication occurred in each treatment group (1%). Primary efficacy was 100% (standard technique), 85% (new device/lidocaine patch) and 73% (new device/lidocaine injection) (P < 0.0001). Secondary efficacy was 100% (standard technique), 92% (new device/lidocaine patch) and 79% (new device/lidocaine injection) (P < 0.0001). Tertiary efficacy was 100% (standard technique), 96% (new device/lidocaine patch) and 91% (new device/lidocaine injection) (P = 0.017). Unsuccessful removals with the new device did not hinder subsequent implant extractions with standard back-up tools. In over 90% of the 150 device procedures, providers agreed or strongly agreed that the product is an acceptable alternative to standard removal technique. LIMITATIONS, REASONS FOR CAUTION: We tested a new removal device in the hands of Ugandan nurses who were adept at standard removal techniques; our estimates of removal efficacy may not apply to lower-level providers who arguably may be the prime beneficiaries of this technology. WIDER IMPLICATIONS OF THE FINDINGS: The study was conducted in a region of the world where the new device could be used to expand access to implant removal services. Intended beneficiaries of the new product are implant users who cannot easily find skilled providers for traditional scalpel-dependent removals and/or users who are intimidated by scalpel procedures, and lower-level providers who can be trained to help deliver services to meet a growing demand. The new device is a safe, acceptable alternative; efficacy was high, but not on par with standard technique. STUDY FUNDING/COMPETING INTEREST(S): Funding for this study was provided by the RemovAid AS of Norway with grants from Research Council of Norway (GLOBVAC number 228319), Bill & Melinda Gates Foundation (grant INV-007571) and SkatteFUNN. M.B. is founder and former CEO of RemovAid AS, Norway. M.B. holds contraceptive rod remover patents (2012 1307156.8 and 2015), pre-removal test (filed) and shares in RemovAid AS. All of the remaining authors' institutions received payments in the form of contracts to help conduct the study; the funds for these contracts emanated from RemovAid AS. TRIAL REGISTRATION NUMBER: NCT04120337. TRIAL REGISTRATION DATE: 9 October 2019. DATE OF FIRST PATIENT'S ENROLMENT: 23 December 2019.

Hand-held device to remove a single-rod subdermal contraceptive implant: Results of early trials in Sweden.

OBJECTIVE: Long-acting reversible contraceptives (LARCs) such as subdermal implants and intrauterine devices are promoted and increasingly used worldwide. Hence, in the light of this we also need to ensure easy access to the reversibility, i.e. emphasise the R in LARC. Our overall aim is to develop a device to facilitate implant removals. We evaluated the safety and performance of the two initial field prototypes where the main outcome was percentage of successful fixations and secondary outcomes were percentage of successful removals without the use of additional tools, duration of the procedure, satisfaction and adverse events. STUDY DESIGN: We performed a feasibility study including 41 subjects. RESULTS: We estimated a fixation rate of 35/41 (85%) and an overall removal rate of 24/41 (59%). Further, we measured that the median time for removals was 80 s and that subjects and operators were satisfied with the procedure. We recorded adverse events such as bruising and superficial abrasions. CONCLUSIONS: The device demonstrated a successful fixation rate, however, the removal rate will need to be further improved. IMPLICATIONS: This feasibility study shows that the device has potential and further research is needed to modify and optimize the device.

Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1ß in non-ST-elevation myocardial infarction.

AIM: To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI). METHODS: 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay. RESULTS: Using a mixed between-within subjects analysis of variance, we observed a significant (p < 0.001) between-group difference in changes for interferon gamma-inducible protein (IP-10) and macrophage inflammatory protein-1ß (MIP-1ß), due to significant increases in the tocilizumab group during hospitalisation (i.e., IP-10 median change from baseline during hospitalisation (mΔ), placebo: 3 (-60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1ß mΔ, placebo: 5 (-2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1ß was inversely correlated to troponin T (r = -0.28, p < 0.05) and neutrophils (r = -0.32, p < 0.05) in the tocilizumab group. In contrast, tocilizumab had only modest or no effects on the other examined cytokines. CONCLUSIONS: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1ß during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074.

Effect of interleukin-6 inhibition on coronary microvascular and endothelial function in myocardial infarction.

OBJECTIVE: Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI). METHODS: This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months. RESULTS: Tocilizumab did not affect CFR during hospitalisation (tocilizumab: 3.4±0.8 vs placebo: 3.3±1.2, p=0.80). CFR improved significantly in both groups at 6 months. Patients in the tocilizumab group had significantly higher area under the curve for VCAM-1 (median 622 vs 609 ng/mL/hour, tocilizumab and placebo respectively, p=0.003). There were inverse correlations between VCAM-1 and CFR in the placebo (hospitalisation: r=-0.74, p<0.01, 6 months: r=-0.59, p<0.01), but not in the tocilizumab group (hospitalisation: r=0.20, p=0.37, 6 months r=-0.28, p=0.20). CONCLUSIONS: Tocilizumab did not affect CFR during hospitalisation or after 6 months. Tocilizumab increased VCAM-1 levels during hospitalisation, but this was not associated with reduced CFR in these patients.

Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial.

AIMS: Interleukin-6 (IL-6) contributes to atherosclerotic plaque destabilization and is involved in myocardial injury during ischaemia-reperfusion. Interleukin-6 is therefore a potential therapeutic target in myocardial infarction (MI). We hypothesized that the IL-6 receptor antagonist tocilizumab would attenuate inflammation, and secondarily reduce troponin T (TnT) release in non-ST-elevation MI (NSTEMI). METHODS AND RESULTS: In a two-centre, double-blind, placebo-controlled trial, 117 patients with NSTEMI were randomized at a median of 2 days after symptom onset to receive placebo (n = 59) or tocilizumab (n = 58), administered as a single dose prior to coronary angiography. High sensitivity (hs) C-reactive protein and hsTnT were measured at seven consecutive timepoints between Days 1 and 3. The area under the curve (AUC) for high-sensitivity C-reactive protein was the primary endpoint. The median AUC for high-sensitivity C-reactive protein during hospitalization was 2.1 times higher in the placebo than in the tocilizumab group (4.2 vs. 2.0 mg/L/h, P < 0.001). Also, the median AUC for hsTnT during hospitalization was 1.5 times higher in the placebo group compared with the tocilizumab group (234 vs. 159 ng/L/h, P = 0.007). The differences between the two treatment groups were observed mainly in (i) patients included ≤2 days from symptom onset and (ii) patients treated with percutaneous coronary intervention (PCI). No safety issues in the tocilizumab group were detected during 6 months of follow-up. CONCLUSION: Tocilizumab attenuated the inflammatory response and primarily PCI-related TnT release in NSTEMI patients.

Long-acting reversible contraception for adolescents and young adults - a cross-sectional study of women and general practitioners in Oslo, Norway.

OBJECTIVES: To investigate awareness and use of long-acting reversible contraceptives (LARCs) in the Norwegian primary care sector. METHODS: We surveyed 359 women aged 16 to 23 years visiting a free sexual health clinic and 140 general practitioners (GPs) in Oslo, Norway, to assess contraceptive usage patterns, knowledge, opinions, and counselling content. RESULTS: Eighty-two percent (n = 295) of the female respondents were current contraceptive users and of this group, 12% (n = 34) were LARC users. Combined oral contraceptives (COCs, 56%) and condoms (20%) were the methods most commonly used. Apart from those two, the women considered themselves insufficiently knowledgeable about other family planning modalities. Knowledge was an independent predictor of current LARC use (p < 0.001). Approximately 35% of GPs often discussed LARC methods when counselling but, due to a lack of implant insertion training, only a few frequently discussed implants during counselling (odds ratio [OR]: 0.12; p = 0.013). The main determinant for not mentioning intrauterine devices and the intrauterine system during counselling was nulliparity (OR: 0.2; p = 0.001 and < 0.001, respectively). CONCLUSION: LARC use is low among 16 to 23-year-olds in Oslo, Norway. These young women need better contraceptive counselling. Dispelling misconceptions and improved provider training could encourage GPs to cover LARCs when giving contraceptive guidance.