Comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'.

A single 300 mg dose of tafenoquine, in combination with chloroquine, is currently approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥16 years. Recently, however, Watson et al. suggested that the approved dose of tafenoquine is insufficient for radical cure, and that a higher 450 mg dose could reduce P. vivax recurrences substantially (Watson et al., 2022). In this response, we challenge Watson et al.'s assertion based on empirical evidence from dose-ranging and pivotal studies (published) as well as real-world evidence from post-approval studies (ongoing, therefore currently unpublished). We assert that, collectively, these data confirm that the benefit-risk profile of a single 300 mg dose of tafenoquine, co-administered with chloroquine, for the radical cure of P. vivax malaria in patients who are not G6PD-deficient, continues to be favourable where chloroquine is indicated for P. vivax malaria. If real-world evidence of sub-optimal efficacy in certain regions is observed or dose-optimisation with other blood-stage therapies is required, then well-designed clinical studies assessing safety and efficacy will be required before higher doses are approved for clinical use.

A flexible multi-metric Bayesian framework for decision-making in Phase II multi-arm multi-stage studies.

We propose a multi-metric flexible Bayesian framework to support efficient interim decision-making in multi-arm multi-stage phase II clinical trials. Multi-arm multi-stage phase II studies increase the efficiency of drug development, but early decisions regarding the futility or desirability of a given arm carry considerable risk since sample sizes are often low and follow-up periods may be short. Further, since intermediate outcomes based on biomarkers of treatment response are rarely perfect surrogates for the primary outcome and different trial stakeholders may have different levels of risk tolerance, a single hypothesis test is insufficient for comprehensively summarizing the state of the collected evidence. We present a Bayesian framework comprised of multiple metrics based on point estimates, uncertainty, and evidence towards desired thresholds (a Target Product Profile) for (1) ranking of arms and (2) comparison of each arm against an internal control. Using a large public-private partnership targeting novel TB arms as a motivating example, we find via simulation study that our multi-metric framework provides sufficient confidence for decision-making with sample sizes as low as 30 patients per arm, even when intermediate outcomes have only moderate correlation with the primary outcome. Our reframing of trial design and the decision-making procedure has been well-received by research partners and is a practical approach to more efficient assessment of novel therapeutics.

Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study.

BACKGROUND: Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin-piperaquine for the radical cure of P vivax malaria. METHODS: In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin-piperaquine alone, dihydroartemisinin-piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin-piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin-piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed. FINDINGS: Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4-22) in patients treated with dihydroartemisinin-piperaquine alone versus 21% (11-34) in patients treated with tafenoquine plus dihydroartemisinin-piperaquine (hazard ratio 0·44; 95% CI [0·29-0·69]) and 52% (37-65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin-piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin-piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin-piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively. INTERPRETATION: Although tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria. FUNDING: ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK. TRANSLATION: For the Indonesian translation of the abstract see Supplementary Materials section.

A pharmacometrics approach to assess the feasibility of capillary microsampling to replace venous sampling in clinical studies: Tafenoquine case study.

AIM: Microsampling has the advantage of smaller blood sampling volume and suitability in vulnerable populations compared to venous sampling in clinical pharmacokinetics studies. Current regulatory guidance requires correlative studies to enable microsampling as a technique. A post hoc population pharmacokinetic (POPPK) approach was utilized to investigate blood capillary microsampling as an alternative to venous sampling. METHODS: Pharmacokinetic data from microsampling and venous sampling techniques during a paediatric study evaluating tafenoquine, a single-dose antimalarial for P. vivax, were used. Separate POPPK models were developed and validated based on goodness of fit and visual predictive checks, with pharmacokinetic data obtained via each sampling technique. RESULTS: Each POPPK model adequately described tafenoquine pharmacokinetics using a two-compartment model with body weight based on allometric scaling of clearance and volume of distribution. Tafenoquine pharmacokinetic parameter estimates including clearance (3.4 vs 3.7 L/h) were comparable across models with slightly higher interindividual variability (38.3% vs 27%) in capillary microsampling-based data. A bioavailability/bioequivalence comparison demonstrated that the point estimate (90% CI) of capillary microsample versus venous sample model-based individual post hoc estimates for area under the concentration-time curve from time zero to infinity (AUC0-inf ) (100.7%, 98.0-103.5%) and Cmax (79.7%, 76.9-82.5%) met the 80-125% and 70-143% criteria, respectively. Overall, both POPPK models led to the same dose regimen recommendations across weight bins based on achieving target AUC. CONCLUSIONS: This analysis demonstrated that a POPPK approach can be employed to assess the performance of alternative pharmacokinetic sampling techniques. This approach provides a robust solution in scenarios where variability in pharmacokinetic data collected via venous sampling and microsampling may not result in a strong linear relationship. The findings also established that microsampling techniques may replace conventional venous sampling methods.

Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial.

BACKGROUND: Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax. METHODS: This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUC[0-∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496. FINDINGS: Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC(0-∞) was 73·8 (90% prediction interval [PI] 46·9-117·0) µg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4-139·0) µg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9-174·0) µg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6-151·0) µg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6-98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study. INTERPRETATION: For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting. FUNDING: GlaxoSmithKline and Medicines for Malaria Venture. TRANSLATIONS: For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

Application of the Stable Isotope Label Approach in Clinical Development-Supporting Dissolution Specifications for a Commercial Tablet Product with Tafenoquine, a Long Half-life Compound.

Bioavailability/bioequivalence studies supporting clinical drug development or commercial supply of drug formulations are often time, cost, and resource intensive. The drug's pharmacokinetic (PK) variability, systemic half-life, and safety issues may pose additional challenges. The stable isotope label (SIL) approach provides a useful tool to significantly reduce the study size in clinical PK studies. Tafenoquine (TQ) is an 8-aminoquinoline under development for preventing Plasmodium vivax malaria relapse. This SIL study assessed the impact of differences in the in vitro dissolution profiles on in vivo exposure of TQ tablets. Fourteen healthy volunteers received a single dose of 300 mg TQ Intermediate Aged or 300 mg TQ Control formulations in this single-center, two-arm, randomized, open-label, parallel-group study. Endpoints included the geometric means ratio of the area under the concentration-time curve (AUC(0-t) and AUC(0-∞); primary endpoint) and maximum plasma concentration (Cmax) for Intermediate Aged versus Control TQ; correlation of PK parameters for venous versus peripheral (via microsample) blood samples; and safety and tolerability endpoints. Geometric mean ratios for PK parameters (AUC and Cmax) and their 90% confidence intervals fell well within standard bioequivalence limits (0.80-1.25). Only one mild adverse event (skin abrasion) was reported. In summary, this SIL methodology-based study demonstrates that the observed differences in the in vitro dissolution profiles between the Control and Intermediate Aged TQ tablets have no clinically relevant effect on systemic TQ exposure. The SIL approach was successfully implemented to enable the setting of a clinically relevant dissolution specification. CLINICAL TRIAL: This study (GSK study number 201780) is registered at clinicaltrials.gov with identifier NCT02751294.

Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety.

Loss of adenosine deaminase activity leads to severe combined immunodeficiency (ADA-SCID); production and function of T, B, and natural killer (NK) cells are impaired. Gene therapy (GT) with an autologous CD34+-enriched cell fraction that contains CD34+ cells transduced with a retroviral vector encoding the human ADA cDNA sequence leads to immune reconstitution in most patients. Here, we report short- and medium-term safety analyses from 18 patients enrolled as part of single-arm, open-label studies or compassionate use programs. Survival was 100% with a median of 6.9 years follow-up (range, 2.3 to 13.4 years). Adverse events were mostly grade 1 or grade 2 and were reported by all 18 patients following GT. Thirty-nine serious adverse events (SAEs) were reported by 15 of 18 patients; no SAEs were considered related to GT. The most common adverse events reported post-GT include upper respiratory tract infection, gastroenteritis, rhinitis, bronchitis, oral candidiasis, cough, neutropenia, diarrhea, and pyrexia. Incidence rates for all of these events were highest during pre-treatment, treatment, and/or 3-month follow-up and then declined over medium-term follow-up. GT did not impact the incidence of neurologic/hearing impairments. No event indicative of leukemic transformation was reported.

A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers.

AIMS: GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent pharmacokinetic (PK) profile across preclinical species (mouse, rat and dog), which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open-label microdose (100 µg, six subjects) first time in humans study was conducted to assess the human PK of GSK3191607 following intravenous administration of [14C]-GSK3191607. METHODS: A human microdose study was conducted to investigate the clinical PK of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in vitro and in vivo pharmacodynamic parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans. RESULTS: The PK profile, based on the microdose data, demonstrated a half-life (~17 h) similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the pharmacodynamic data provided results that do not support further clinical development of the compound for a single dose cure. CONCLUSIONS: The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound.

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency is a rare, autosomal-recessive systemic metabolic disease characterized by severe combined immunodeficiency (SCID). The treatment of choice for ADA-deficient SCID (ADA-SCID) is hematopoietic stem cell transplant from an HLA-matched sibling donor, although <25% of patients have such a donor available. Enzyme replacement therapy (ERT) partially and temporarily relieves immunodeficiency. We investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Patients were treated with an autologous CD34(+)-enriched cell fraction that contained CD34(+) cells transduced with a retroviral vector encoding the human ADA complementary DNA sequence (GSK2696273) as part of single-arm, open-label studies or compassionate use programs. Overall survival was 100% over 2.3 to 13.4 years (median, 6.9 years). Gene-modified cells were stably present in multiple lineages throughout follow up. GT resulted in a sustained reduction in the severe infection rate from 1.17 events per person-year to 0.17 events per person-year (n = 17, patient 1 data not available). Immune reconstitution was demonstrated by normalization of T-cell subsets (CD3(+), CD4(+), and CD8(+)), evidence of thymopoiesis, and sustained T-cell proliferative capacity. B-cell function was evidenced by immunoglobulin production, decreased intravenous immunoglobulin use, and antibody response after vaccination. All 18 patients reported infections as adverse events; infections of respiratory and gastrointestinal tracts were reported most frequently. No events indicative of leukemic transformation were reported. Trial details were registered at www.clinicaltrials.gov as #NCT00598481.

A Retrospective, Pooled Suicidality Evaluation of Ropinirole Immediate Release and Controlled Release for the Treatment of Restless Legs Syndrome.

PURPOSE: Based on an internal request, GlaxoSmithKline conducted a retrospective pooled analysis of randomized controlled trials to compare suicidality in adult subjects with restless legs syndrome (RLS) who were being treated with ropinirole. The objective was to proactively evaluate the incidence of potentially suicidal thoughts or behaviors (suicidality) among patients with RLS treated with ropinirole immediate release (IR) or controlled release (CR). METHODS: The US Food and Drug Administration approved methods previously used for the retrospective analysis of suicidality with antidepressants and anticonvulsants. Potential cases of suicidal thoughts and behavior were identified from searches of treatment-emergent adverse event preferred and verbatim terms; a review of serious adverse events; and searches of a priori-identified free text comment fields in the case report forms. Blinded case reports for these potential cases, in addition to all serious adverse events, were categorized by using the Columbia Classification Algorithm of Suicide Assessment. FINDINGS: The dataset for this study comprised 1799 patients who received ropinirole (either formulation) and 1258 patients who received placebo. No signal for suicidality was detected for ropinirole in the treatment of patients with RLS. IMPLICATIONS: The pooled datasets in this study were not designed to prospectively assess for suicidal ideation or behavior. Any future studies in this area should include the collection of prespecified, detailed information regarding suicidality.

Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study.

BACKGROUND: Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys. Antisense-oligonucleotide-induced exon skipping allows synthesis of partially functional dystrophin. We investigated the efficacy and safety of drisapersen, a 2'-O-methyl-phosphorothioate antisense oligonucleotide, given for 48 weeks. METHODS: In this exploratory, double-blind, placebo-controlled study we recruited male patients (≥5 years of age; time to rise from floor ≤7 s) with Duchenne muscular dystrophy from 13 specialist centres in nine countries between Sept 1, 2010, and Sept 12, 2012. By use of a computer-generated randomisation sequence, we randomly allocated patients (2:2:1:1; block size of six; no stratification) to drisapersen 6 mg/kg or placebo, each given subcutaneously and either continuously (once weekly) or intermittently (nine doses over 10 weeks). The primary endpoint was change in 6-min walk distance (6MWD) at week 25 in patients in the intention-to-treat population for whom data were available. Safety assessments included renal, hepatic, and haematological monitoring and recording of adverse events. This trial is registered with ClinicalTrials.gov, number NCT01153932. FINDINGS: We recruited 53 patients: 18 were given continuous drisapersen, 17 were given intermittent drisapersen, and 18 were given placebo (continuous and intermittent groups combined). At week 25, mean 6MWD had increased by 31·5 m (SE 9·8) from baseline for continuous drisapersen, with a mean difference in change from baseline of 35·09 m (95% CI 7·59 to 62·60; p=0·014) versus placebo. We recorded no difference in 6MWD changes from baseline between intermittent drisapersen (mean change -0·1 [SE 10·3]) and placebo (mean difference 3·51 m [-24·34 to 31·35]) at week 25. The most common adverse events in drisapersen-treated patients were injection-site reactions (14 patients given continuous drisapersen, 15 patients given intermittent drisapersen, and six given placebo) and renal events (13 for continuous drisapersen, 12 for intermittent drisapersen, and seven for placebo), most of which were subclinical proteinuria. None of the serious adverse events reported (one for continuous, two for intermittent, and two for placebo) resulted in withdrawal from the study. INTERPRETATION: Continuous drisapersen resulted in some benefit in 6MWD versus placebo at week 25. The safety findings are similar to those from previous studies. Ambulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies. FUNDING: GlaxoSmithKline, Prosensa Therapeutics BV (a subsidiary of Prosensa Holding NV).

Sleep Duration and "on" Time during Different Periods of the Day and Night in Patients with Advanced Parkinson's Disease Receiving Adjunctive Ropinirole Prolonged Release.

Patients undergoing long-term therapy for PD often experience motor fluctuations and nocturnal disturbances. In a post-hoc analysis, we explored effects of ropinirole prolonged release on sleep, night-time awakenings, and "on" time over 24 hours. Patients with advanced PD suboptimally controlled with L-dopa were randomized to adjunctive ropinirole prolonged release (2-24 mg/day) or placebo for 24 weeks. Awake/asleep and, if awake, "on"/"off" status was recorded via diary cards. At week 24 last observation carried forward, changes in nighttime or daytime sleep duration were not significantly different between treatments. Of patients with baseline awakenings, a significantly higher proportion in the ropinirole prolonged release group had a reduction in awakenings versus placebo. Patients receiving ropinirole prolonged release had a significantly greater increase in amount/percentage of awake time "on"/"on" without troublesome dyskinesia during all periods assessed (including night-time and early morning), versus placebo, and higher odds for being "on" on waking. Adjunctive once-daily ropinirole prolonged release may help provide 24-hour symptom control in patients with advanced PD not optimally controlled with L-dopa.

Investigating variability in patient response to treatment--a case study from a replicate cross-over study.

It is a common belief that individual variation in response to treatment is an important explanation for the variation in observed outcomes in clinical trials. If such variation is large, it seems reasonable to suppose that progress in treating disease will be advanced by classifying patients according to their abilities or not to 'respond' to particular treatments. We consider that there is currently a lost opportunity in drug development. There is a great deal of talk about individual response to treatment and tailor-made drugs. However, relatively little work is being done to formally investigate, using suitable designs, where individual response to treatment may be important. Through a case study from a replicate cross-over study we show how, given suitable replication, it is possible to isolate the component of variation corresponding to patient-by-treatment interaction and hence investigate the possibility of individual response to treatment.