The current treatment regimen against drug susceptible tuberculosis (DS-TB) was defined by the 1980s. Since then the emergence of the global HIV pandemic and the escalation of drug resistant (DR−) forms of TB have presented new challenges for therapeutic research. Priority goals include shortening DS-TB treatment, improving DR-TB treatment and making combined TB-HIV therapy easier. To help achieve these goals, a range of new drugs and treatment strategies are currently being evaluated. Phase IIb and III clinical trials are ongoing to assess combinations involving the high-dose rifamycins, the 8-methoxyquinolones, a diarylquinoline (bedaquiline) and the nitroimidazoles. Other compounds (e.g. novel oxazolidinones and ethylenediamines) are at earlier stages of clinical development. Overall, there are grounds for optimism that recent advances will contribute towards achievement of new treatment regimens in the foreseeable future. However, long-term investment, political commitment and scientific endeavour are crucial to ensure that progress is sustained and the benefits of recent advances reach those in the greatest need.
IntroductionThe approved dose of tenofovir disproxil fumarate, 300 mg once daily, was established in clinical trials in combination with efavirenz, which does not significantly affect tenofovir concentrations. Combining tenofovir with lopinavir/r, darunavir/r or atazanavir/r increases tenofovir concentrations, which could raise the risk of renal adverse events. Newly approved tenofovir tablets are available at lower strength (200 or 250 mg) for use in paediatrics.MethodsA literature search was used to assess the effects of lopinavir/r, darunavir/r and atazanavir/r on tenofovir plasma Cmax, AUC and Cmin (Geometric Mean Ratio and 90% confidence intervals). Assuming linear dose‐proportional pharmacokinetics (as observed in dose‐ranging studies), the 250 mg tablet was predicted to achieve plasma concentrations 17% lower than the 300 mg dose, and the 200 mg tablet to achieve plasma levels 33% lower. Effects on tenofovir plasma Cmax, AUC and Cmin concentrations were assessed for combined dosing of each protease inhibitor with 250 or 200 mg daily doses of tenofovir, versus standard dose tenofovir (300 mg daily) without protease inhibitors.ResultsIn drug‐drug interaction studies, lopinavir/ritonavir significantly increased tenofovir Cmax, AUC and Cmin. Effects of each PI on tenofovir Cmin were greater than effects on Cmax or AUC. Using a 250 mg paediatric dose of tenofovir with lopinavir/ritonavir, tenofovir Cmin was predicted to remain higher than tenofovir 300 mg used with efavirenz (GMR=1.26, 95% CI 1.14–1.38). Similar results were observed for use of tenofovir 250 mg with atazanavir/ritonavir (GMR=1.07, 95% CI 1.01–1.13) and with darunavir/ritonavir (GMR=1.14, 95% CI 0.99–1.31). Predicted tenofovir AUC levels for the 250 mg dose with protease inhibitors were all within the bioequivalence range, relative to use with efavirenz. Using a 200 mg paediatric dose of tenofovir with lopinavir/ritonavir, the tenofovir Cmin was predicted to be bioequivalent to tenofovir 300 mg used with efavirenz (GMR=1.02, 95% CI 0.92–1.11). Similar results were observed for use of tenofovir 200 mg with atazanavir/ritonavir (GMR=0.86, 95% CI 0.82–0.91) and with darunavir/ritonavir (GMR=0.92, 95% CI 0.80–1.05). All three results were within the bioequivalence limits of 0.8–1.25.ConclusionsUse of approved paediatric doses of tenofovir (200–250 mg once daily) in combination with lopinavir/r,darunavir/r or atazanavir/r could compensate for known drug interactions. This dose modification could potentially improve renal safety.
IntroductionTreatment of HIV/TB co‐infection is challenging due to high drug–drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF). The PK interaction between darunavir/ritonavir (DRV/RTV) and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV/RTV PK and generate alternative dosing strategies to aid future clinical trial design.Materials and MethodsA previously developed model describing DRV/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV/RTV 800/100 mg (n=32) or 900/100 mg once daily (qd; n=19) [1]. The PK interaction between DRV/RTV and RIF was assumed to mimic that observed in HIV‐infected, TB negative patients receiving lopinavir (LPV)/RTV (n=21) [2]. Simulations of DRV/RTV 800/100 mg qd (n=1000) were performed (‐RIF). The model was adapted to increase the typical value of apparent oral clearance (CL/F) by 71% and 36% and decrease relative bioavailability (F) by 20% and 45% for DRV and RTV, respectively [2]; 1000 simulations were generated (+RIF). Dose adjustments of DRV/RTV 1200/200 mg qd, 800/100 mg and 1200/150 mg twice daily (bid) were simulated to overcome the interaction. DRV trough (Ctrough) for each dosing scenario was compared to the reference (‐RIF) by GMR (90% CI).ResultsDRV and RTV were described by a 1 and 2‐compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL/F, best described the relationship between the drugs. Compared to the reference (‐RIF), simulated DRV Ctrough was 70%, 46% and 20% lower for 800/100 mg qd, 1200/200 mg qd and 800/100 mg bid all +RIF, respectively. Ctrough was 38% higher with 1200/150 mg bid +RIF (Table 1).ConclusionsModelling and simulation was used to investigate the theoretical impact of RIF on DRV/RTV PK. Based on simulations, 800/100 mg and 1200/150 mg both bid could largely overcome the impact of the interaction. However, the risk of increased RTV‐related side effects and higher pill burden should be considered. In vitro work is ongoing to develop a physiologically based model characterizing the interaction and informing simulations.
IntroductionThere have been several important developments in antiretroviral treatment in the past two years. Randomized clinical trials have been conducted to evaluate a lower dose of efavirenz (400 mg once daily). Integrase inhibitors such as dolutegravir have been approved for first‐line treatment. A new formulation of tenofovir (alafenamide) has been developed and has shown equivalent efficacy to tenofovir in randomized trials. Two‐drug combination treatments have been evaluated in treatment‐naïve and ‐experienced patients. The novel pharmacokinetic booster cobicistat has been compared to ritonavir in terms of pharmacokinetics, efficacy and safety. The objective of this commentary is to assess recent developments in antiretroviral drug treatment to determine whether new treatments should be included in new international guidelines.DiscussionThe use of first‐line treatment with tenofovir and efavirenz at the standard 600 mg once‐daily dose should remain the first‐choice standard of care treatment. Evidence supporting a switch to efavirenz 400 mg once daily or integrase inhibitors is sufficient to consider these drugs as alternative first‐line options, but more data are needed on their use in pregnant women and people with TB co‐infection. The use of new formulations of tenofovir is currently too preliminary to justify immediate adoption and scale‐up across HIV programmes in low‐ and middle‐income countries. The evidence supporting use of two‐drug combinations is not considered strong enough to justify changed recommendations from use of standard triple drug combinations. Cobicistat does not offer significant safety advantages over ritonavir as a pharmacokinetic booster.ConclusionsFor continued scale‐up of antiretroviral treatment in low‐ and middle‐income countries, use of first‐line triple combinations including efavirenz 600 mg once daily is supported by the largest evidence base. Additional studies are underway to evaluate new treatments in key populations, and these results may justify changes to these recommendations.
IntroductionAntiretroviral therapy is recommended during pregnancy for prevention of mother‐to‐child transmission (MTCT) of HIV. Physiological changes during pregnancy are known to affect the pharmacokinetics (PK) of protease inhibitors (PIs), leading to lower exposures in pregnant women. Here we examine the PK of DRV/r 800/100 mg once daily (OD) over the course of pregnancy and postpartum (PP).Material and MethodsIn this prospective open‐labelled study, HIV‐positive pregnant women receiving darunavir/ritonavir as part of their routine maternity care were enrolled. DRV plasma trough concentrations [DRV] were determined in the first (T1) and/or second (T2) and/or third (T3) trimester and PP using a validated HPLC‐MS/MS methodology (Lab21, Cambridge UK). Where possible paired maternal and cord blood samples were taken at delivery.ResultsTo date 20 women (12 black African, 8 Caucasian) have been enrolled. Median (range) baseline CD4 count was 338 cells/µL (108–715), and median baseline plasma viral load was 555 copies/mL (<40–8,188,943). All but 2 women were virally suppressed at time of delivery (114 and 176 copies/mL; 1 sub‐therapeutic at T3) and median CD4 count was 410 cells/µL (92–947). There were 20 live births, all term deliveries and there were no cases of MTCT. [DRV] (geometric mean; 95% CI) was 3790 ng/mL at T1 (n=1); 1288 ng/mL (663–1913) at T2 (n=9); 1086 ng/mL (745–1428) at T3 (n=18, 1 undetectable) and 2324 ng/mL (1369–3279) at PP (n=14, 1 undetectable). There was no significant difference in [DRV] between T2 and PP (p=0.158); however, there was between T3 and PP (p=0.021). Nineteen of twenty (95%) and 16 of 20 (80%) women achieved [DRV] above the estimated MEC for WT (55 ng/mL) and PI resistant HIV‐1 (550 ng/mL) throughout pregnancy. Maternal and cord [DRV] were available for 10 mother–baby pairs. Mean maternal [DRV] at delivery was 2235 ng/mL (±1557 ng/mL), while mean cord [DRV] was 337 ng/mL (±217 ng/mL). The median cord to maternal blood ratio (C/M) was 0.11 (0.06–0.49).ConclusionsIn most cases examined, DRV/r 800/100 mg once daily was effective at achieving adequate therapeutic drug levels (>550 ng/ml) during pregnancy. However, reduced DRV plasma concentrations in the second/third trimesters highlights the need for TDM in this population and warrants further study of pregnancy‐associated changes in DRV pharmacokinetics. The low C/M ratios reported here are consistent with previous reports [1] and suggest low transplacental transfer of DRV.
IntroductionSub‐dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long‐acting contraception, but their use among HIV‐positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A‐mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub‐dermal implant over six months in HIV‐positive Ugandan women on nevirapine (NVP)‐ or efavirenz (EFV)‐based ART.Material and MethodsThis non‐randomized, parallel group study compared LNG pharmacokinetics between HIV‐positive Ugandan women not yet eligible for ART (control group, n=18) and those on stable NVP‐ (n=20) or EFV‐ (n=20) based ART. The two‐rod (75 mg/rod) LNG sub‐dermal implant was inserted at study enrolment. LNG sampling was obtained pre‐implant and at weeks 1, 4, 12 and 24 post‐insertion. LNG concentrations were analyzed using a validated LC‐MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit.ResultsAt enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm3, respectively; p=0.09); all women in the NVP and EFV groups had an undetectable HIV‐RNA. Women in the control group had a higher baseline body weight (73 kg) compared to those in the NVP (63 kg; p=0.03) or EFV groups (60 kg; p<0.01). By linear regression, weight was a significant predictor of LNG concentrations (1 kg increase in weight=5 pg/mL decrease in LNG, p=0.03). LNG concentrations are reported in the table.ConclusionsOver a 24‐week period, LNG concentrations were 40–54% lower in women on EFV‐based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP‐based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially explained by body weight. These data confirm a significant drug interaction occurs between the LNG implant and EFV, adding to growing concern for reduced contraceptive efficacy with their combined use. In contrast, these data support use of the LNG implant with NVP‐based ART.
AbstractIntroductionTo adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure.DiscussionThe article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non‐pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in non‐pregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours.ConclusionsA formalized step‐wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research – the use of newer, more effective drugs in women is at stake (349).
AbstractIntroductionWomen who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available.DiscussionThe World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year‐long workshop on "Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women." Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre‐ and post‐licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non‐pregnant adults, provided that drug levels in pregnancy are similar. However, short‐term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre‐clinical studies is essential for pregnancy short‐term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post‐marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two‐drug regimens, long‐acting ARVs and ARVs administered through novel delivery systems.ConclusionsImplementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.
OBJECTIVES: The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. TRIAL DESIGN: GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. PARTICIPANTS: This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have >=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as: • greater than Child-Pugh grade A • AST or ALT > 5 x ULN • AST or ALT >3 x ULN and Total Bilirubin > 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. MAIN OUTCOMES: The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). RANDOMISATION: Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI>30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). BLINDING (MASKING): No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. TRIAL STATUS: The current GETAFIX protocol is version 4.0 12th September 2020. GETAFIX opened to recruitment on 26th October 2020 and will recruit patients over a period of approximately six months. TRIAL REGISTRATION: GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15th April 2020; Reference number 2020-001904-41 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB ). GETAFIX was registered on ISRCTN on 7th September 2020; Reference number ISRCTN31062548 ( https://www.isrctn.com/ISRCTN31062548 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2).
Objectives: The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. Trial design: GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. Participants: This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have >=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as: • greater than Child-Pugh grade A • AST or ALT > 5 x ULN • AST or ALT >3 x ULN and Total Bilirubin > 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Intervention and comparator: Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. Main outcomes: The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). Randomisation: Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI>30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). Blinding (masking): No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. Numbers to be randomised (sample size): In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. Trial Status: The current GETAFIX protocol is version 4.0 12th September 2020. GETAFIX opened to recruitment on 26th October 2020 and will recruit patients over a period of approximately six months. Trial registration: GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15th April 2020; Reference number 2020-001904-41 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB). GETAFIX was registered on ISRCTN on 7th September 2020; Reference number ISRCTN31062548 (https://www.isrctn.com/ISRCTN31062548). Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2).
AbstractIntroductionPregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand‐alone protocols, platform trials, single arm studies, sample size and the effect that follow‐up time during gestation has on analysis interpretations; and observational studies.DiscussionPregnancy PK should be studied during drug development, after dosing in non‐pregnant persons is established (unless non‐clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand‐alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand‐alone pregnancy trial protocols can include pre‐specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost‐prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias.ConclusionsPregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high‐priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.
AbstractIntroductionThe unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk‐benefit messaging when a safety signal is identified.DiscussionThe Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll‐out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high‐quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified.ConclusionsThe response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk‐benefit trade‐offs in a variety of contexts; guidance to transform this risk‐benefit balance into effective and agreed‐upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.
