A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics. PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28. FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection. INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS. TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.

Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial.

BACKGROUND: Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. METHODS: BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. RESULTS: Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. CONCLUSIONS: The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

Correction: Bailey et al. Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial. Cancers 2022, 14, 374.

In the original publication [...].

Efficacy and optimal dose of acetic acid to treat colonised burns wounds: protocol for a pilot randomised controlled trial.

INTRODUCTION: Despite of recent advancement in the burns wound management, burn wound infection (BWI) is still one of the major cause of burns mortality. Patients who survive their burns injury still suffers from BWI related complication like delayed wound healing and poor scarring. BWI has been treated by application of topical antimicrobial agents or systemic antibiotics. Due to the global risk of developing systemic antibiotics resistance, medical research focuses on identifying single topical agent which has effective antimicrobial activity, easily available and cost effective. One such agent is acetic acid (AA). AA has been used as a topical antibacterial agent for the treatment of burns wounds for many years and has shown to have activity against gram-negative organisms including Pseudomonas aeruginosa. So far there has been no consensus on optimal concentration that has effective antimicrobial activity, frequency of application, duration of treatment and most importantly good patient's tolerability. A randomised control study is required to answer all these questions. OBJECTIVE: To investigate the efficacy and tolerability of 0.5% and 2% of AA when applied to colonised burns wounds for 3 days after admittance to the Queen Elizabeth Hospital Birmingham. METHODS AND ANALYSIS: This is a double-blinded, prospective, randomised, controlled, single-centre trial. Patients will be screened for eligibility in the inpatient area and those who are found to be eligible will be randomly assigned to one of two treatment groups: group 1: 0.5% AA (10 patients); group 2: 2% AA (10 patients); total number: 20 patients. OUTCOME MEASURES: Primary outcome: Efficacy will be assessed by measuring the bacterial load from microbiology wound swabs for three consecutive days.Secondary outcomes: (1) The assessment of antimicrobial activity of AA and the minimum inhibitory concentrations. (2) Patient's tolerance by assessing Visual Analogue Scale pain score. (3) Time to 95% wound healing of treatment area. (4) Patient's perceived treatment allocation. ETHICS AND DISSEMINATION: AceticA trial protocol was approved by the National Research Ethics Service (West Midlands-Edgbaston Research Ethics Committee; 17/WM/0407; IRAS 234132). This article refers to protocol version 5.0 dated 6 July 2020. The analysed results will be presented at national and international conferences related to management of burn patients. The generated articles based on the trial results will be submitted to peer review journals for publication. TRIAL REGISTRATION NUMBER: ISRCTN11636684.

Defining estimands for efficacy assessment in single arm phase 1b or phase 2 clinical trials in oncology early development.

The addendum of the ICH E9 guideline on the statistical principles for clinical trials introduced the estimand framework. The framework is designed to strengthen the dialog between different stakeholders, to introduce greater clarity in the clinical trial objectives and to provide alignment between the estimand and statistical analysis. Estimand framework related publications thus far have mainly focused on randomized clinical trials. The intention of the Early Development Estimand Nexus (EDEN), a task force of the cross-industry Oncology Estimand Working Group (www.oncoestimand.org), is to apply it to single arms Phase 1b or Phase 2 trials designed to detect a treatment-related efficacy signal, typically measured by objective response rate. Key recommendations regarding the estimand attributes include that in a single arm early clinical trial, the treatment attribute should start when the first dose is received by the participant. Focusing on the estimation of an absolute effect, the population-level summary measure should reflect only the property used for the estimation. Another major component introduced in the ICH E9 addendum is the definition of intercurrent events and the associated possible ways to handle them. Different strategies reflect different clinical questions of interest that can be answered based on the journeys an individual subject can take during a trial. We provide detailed strategy recommendations for intercurrent events typically seen in early-stage oncology. We highlight where implicit assumptions should be made transparent as whenever follow-up is suspended, a while-on-treatment strategy is implied.

Defective T-cell response to COVID-19 vaccination in acute myeloid leukaemia and myelodysplastic syndromes.

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.

Longitudinal prospective cohort study evaluating prognosis in idiopathic intracranial hypertension patients with and without comorbid polycystic ovarian syndrome.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) and polycystic ovary syndrome (PCOS) are hyperandrogenic metabolic disorders that affect women of reproductive age living with obesity. The previously reported prevalence of comorbid PCOS in IIH patients is highly variable and the longitudinal impact on visual and headache outcomes are unknown. METHODS: In this prospective longitudinal cohort study patients were identified from the IIH: Life database over a nine-year period (2012-2021). Data collected included demographics and PCOS questionnaire data. Key visual and detailed headache outcomes were recorded. We analysed the key variables for influential outcomes of vision and headache. Logistical regression methods were used to model long term visual and headache outcomes. RESULTS: Overall 398 women with IIH and documented PCOS questionnaires were followed up for a median of 10 months (range 0-87). Prevalence of PCOS in IIH was 20% (78/398) diagnosed by the Rotterdam criteria. Patients with IIH and comorbid PCOS reported higher self-reported fertility problems (3.2-fold increased risk) and increased need for medical help in becoming pregnant (4.4-fold increased risk). Comorbid PCOS in IIH patients does not adversely impact long-term vision or headache outcomes. The headache burden was high in both cohorts studied. CONCLUSIONS: The study demonstrated that comorbid PCOS in IIH is common (20%). Diagnosing comorbid PCOS is important as it can impact on fertility and is known to have long-term adverse cardiovascular risks. Our data suggest that a diagnosis of PCOS in those with IIH does not significantly exacerbate long-term vision or headache prognosis.

Asymptomatic idiopathic intracranial hypertension: Prevalence and prognosis.

BACKGROUND: Little is known about the presentation and prognosis of asymptomatic idiopathic intracranial hypertension (IIH). Papilloedema can be found incidentally on routine fundus examination, with many of these patients actually having symptoms on direct questioning. The aim was to evaluate visual and headache outcomes in people with IIH who present with or without symptoms. METHODS: Prospective observational cohort study, between 2012 and 2021, 343 people with confirmed IIH diagnosis were enrolled in the IIH:Life database. Outcomes such as vision (LogMAR); Humphrey visual field perimetric mean deviation (PMD) and optical coherence tomography (OCT) and headache were evaluated using LOESS (locally weighted scatterplot smoothing) graphs and regression analysis. RESULTS: One hundred and twenty-one people had incidentally found papilloedema, with 36 people with completely asymptomatic presentations. Those with asymptomatic IIH at diagnosis had similar visual prognosis compared to those with symptomatic disease. Sixty-six percent of the asymptomatic cohort became symptomatic during follow-up, and of these the predominant symptom was headache (96%). Headache frequency during follow-up was lower in the asymptomatic cohort. CONCLUSIONS: The prognosis of those with IIH who present with or without symptoms is similar.

Disease Course and Long-term Outcomes in Pregnant Women With Idiopathic Intracranial Hypertension: The IIH Prospective Maternal Health Study.

BACKGROUND AND OBJECTIVES: Idiopathic intracranial hypertension (IIH) most typically occurs in women of childbearing age with increased weight as a key risk factor for development or exacerbation of the disease. Pregnancy is common in this group of patients. The longer-term effect of pregnancy on IIH has not been established and was the aim of this study. METHODS: A prospective cohort study (IIH Life) recruited consecutive patients with IIH between 2012 and 2021 and evaluated outcomes including vision (logarithm of the minimum angle of resolution visual acuity, Humphrey visual field perimetric mean deviation, and optical coherence tomography [OCT] imaging) and headache. Four cohorts were evaluated: those with IIH diagnosed for the first time while pregnant, those with established IIH who became pregnant, those with a pregnancy prior to their diagnosis of IIH, and those with IIH who never became pregnant. RESULTS: Three hundred seventy-seven people with IIH agreed to participate in the IIH Life maternal health study. Mean follow-up was 17.5 months (SD 20.5). IIH diagnosed in pregnancy was rare. Patients diagnosed with IIH while pregnant had greater papilledema (mean OCT total retinal thickness +11.59 µm/mo [95% CI 1.25-21.93]), although they had comparable visual field and acuity measures compared with those with established IIH who became pregnant during their disease course (-1.2 µm/mo [95% CI -2.6 to 0.21]). In those with established IIH, pregnancy did not adversely affect visual or headache outcomes over time, and the trajectory was akin to those with IIH who never had a pregnancy. Headache outcomes showed variability reflecting the IIH cohort as a whole. DISCUSSION: A diagnosis of IIH while pregnant was rare but associated with more severe papilledema. Long-term visual outcomes in IIH were analogous irrespective of the timing of the pregnancy. These data are reassuring; however, close vigilance of IIH clinical features during pregnancy is recommended.

Defining the Phenotype and Prognosis of People With Idiopathic Intracranial Hypertension After Cerebrospinal Fluid Diversion Surgery.

PURPOSE: To characterize the phenotype of patients with idiopathic intracranial hypertension (IIH) who received cerebrospinal (CSF) diversion surgery and to detail the trajectory of recovery. DESIGN: Prospective cohort registry study. METHODS: Patients with IIH with sight-threatening papilledema presenting to a single United Kingdom neuroscience center between 2019 and 2021 were included. Outcomes consisted of perimetric mean deviation (PMD) and optical coherence tomography measures of papilledema (retinal nerve fiber layer [RNFL]) and macular ganglion cell layer (GCL) in both eyes. Headache outcomes included monthly headache days (MHD). Logistic regression methods were used to model long-term outcomes. RESULTS: Fifty-one patients without previous surgical interventions were included (92% female, mean age 28.1 years [SD 8.4], body mass index 37.4 kg/m2 [SD 9.7], mean days of follow-up 330 [SD 209]). Measurements before surgery showed mean PMD -11.4 dB (SD 9.7), RNFL 364 µm (SD 128), Frisén grade papilledema 4.3 (SD 0.9). and MHD 23 (SD 10.6). At 1 month postoperatively, RNFL and PMD had improved by 38% and 4%, respectively. At 4 months postoperatively, papilledema had resolved. GCL declined by 13% over 12 months. MHD reduced by 75% 3 months postoperatively before returning to baseline levels by 12 months. Five patients (9.8%) required revision surgeries. CONCLUSIONS: Detailed characteristics of patients with sight-threatening IIH who received CSF diversion surgery and their typical postoperative recovery are presented. These parameters should guide physicians as to when patients with IIH may require surgery and enable the early identification of outliers who fail to respond. Papilledema and PMD recovered but GCL atrophy continued for 12 months. The implication of this delayed atrophy is unknown.

The idiopathic intracranial hypertension prospective cohort study: evaluation of prognostic factors and outcomes.

BACKGROUND: There are limited longitudinal data evaluating outcomes in idiopathic intracranial hypertension (IIH). We aimed to evaluate the long-term outcomes in a real-world cohort of patients with IIH and sought to establish the prognostic factors. METHODS: A longitudinal prospective cohort study was conducted over 9 years (2012-2021). Data included demographics and disease status. All consenting patients with IIH were recruited. Visual outcomes included visual acuity, Humphrey visual field and optical coherence tomography (OCT) imaging measurements. Headache frequency, severity, and impact were noted. We analysed the key variables impacting visual and headache outcomes. RESULTS: The cohort contained 490 patients with a confirmed IIH diagnosis. 98% were female with a mean body mass index (BMI) of 38 kg/m2. Those with the highest OCT retinal nerve fibre layer had the worst visual outcomes. We noted a delayed decline, in the visual field and OCT ganglion cell layer after 12 months. In the medically managed cohort (n = 426), we found that disease duration and change in BMI had the greatest influence on visual outcomes. There was a high burden of headache, with a daily headache at presentation and prior migraine history influencing long-term headache prognosis. CONCLUSIONS: There is a delayed decline in visual outcomes in those with the most severe papilloedema. Disease duration and change in BMI were the key visual prognostic factors, therefore those with the more acute disease may require closer monitoring. Improving prognosis in IIH should focus on the potentially modifiable factor of weight management.

Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision.

BACKGROUND: Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84-99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group. METHODS: Patients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference cohort of aged-matched controls from the UK general population. This study is registered with the ISRCTN registry, ISRCTN14422743, and is closed. FINDINGS: Between July 21, 2011, and July 15, 2015, 88 patients were enrolled onto the TREC study to undergo organ preservation, of whom 27 (31%) were randomly allocated to organ-preserving therapy and 61 (69%) were added to the non-randomised registry for organ-preserving therapy. Non-randomised patients were older than randomised patients (median age 74 years [IQR 67-80] vs 65 years [61-71]). Organ-preserving treatment was well tolerated among patients in the non-randomised registry, with mild worsening of fatigue; quality of life; physical, social, and role functioning; and bowel function 3 months postoperatively compared with baseline values. By 6-12 months, most scores had returned to baseline values, and were indistinguishable from data from the reference cohort. Only mild symptoms of faecal incontinence and urgency, equivalent to less than one episode per week, persisted at 36 months among patients in both groups. INTERPRETATION: The SCRT and TEM organ-preservation approach was well tolerated in older and frailer patients, showed good rates of organ preservation, and was associated with low rates of acute and long-term toxicity, with minimal effects on quality of life and functional status. Our findings support the adoption of this approach for patients considered to be at high risk from radical surgery. FUNDING: Cancer Research UK.

Topical treatment of actinic keratoses in organ transplant recipients: a feasibility study for SPOT (Squamous cell carcinoma Prevention in Organ transplant recipients using Topical treatments).

BACKGROUND: The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients. OBJECTIVES: To assess the feasibility, activity and evaluation outcomes relevant to the design of a future phase III RCT of topical cSCC chemoprevention in OTRs. METHODS: OTRs with 10 or more AKs in predefined areas were randomized 1 : 1 : 1 to topical 5-FU, 5% imiquimod (IMIQ) or sunscreen (sun-protective factor 30+) in a phase II, open-label RCT over 15 months. Feasibility outcomes included proportions of eligible OTRs randomized, completing treatment and willing to be re-treated. AK activity [AK clearance, new AK development, patient-centred outcomes (toxicity, health-related quality of life, HRQoL)] and evaluation methodology (clinical vs. photographic) were assessed. RESULTS: Forty OTRs with 903 AKs were randomized. All feasibility outcomes were met (56% of eligible OTRs were randomized; 89% completed treatment; 81% were willing to be re-treated). AK activity analyses found 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs. 5-FU was more effective than IMIQ in AK clearance and prevention in exploratory analyses. Although toxicity was greater with 5-FU, HRQoL outcomes were similar. CONCLUSIONS: Trials of topical AK treatments in OTRs for cSCC chemoprevention are feasible and AK activity results support further investigation of 5-FU-based treatments in future phase III trials. What is already known about this topic? Cutaneous squamous cell carcinoma (cSCC) is significantly more common in immunocompromised individuals including organ transplant recipients (OTRs) compared with immunocompetent populations. cSCC chemoprevention activity of sunscreen and 5-fluorouracil-based (5-FU) actinic keratosis (AK) treatments has been demonstrated in randomized controlled trials (RCTs) in immunocompetent populations but not in OTRs. AKs are cSCC precursors and their clearance and prevention are generally regarded as surrogate endpoint biomarkers for potential cSCC chemoprevention activity. What does this study add? SPOT (SCC Prevention in OTRs using Topical treatments) has confirmed that RCTs of OTR-cSCC chemoprevention with topical AK treatments are feasible. It also suggests that topical 5-FU may be superior to 5% imiquimod and sunscreen in AK clearance and prevention. Together with recent evidence from several RCTs in the general population, these data provide a compelling rationale for further studies of intervention with 5-FU-based topical chemoprevention approaches in OTR-cSCC prevention.

A prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its Profile in Trauma: ADaPT.

INTRODUCTION: The improvements in short-term outcome after severe trauma achieved through early resuscitation and acute care can be offset over the following weeks by an acute systemic inflammatory response with immuneparesis leading to infection, multiorgan dysfunction/multiorgan failure (MOF) and death. Serum levels of the androgen precursor dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, steroids with immune-enhancing activity, are low after traumatic injury at a time when patients are catabolic and immunosuppressed. Addressing this deficit and restoring the DHEA(S) ratio to cortisol may provide a range of physiological benefits, including immune modulatory effects. OBJECTIVE: Our primary objective is to establish a dose suitable for DHEA supplementation in patients after acute trauma to raise circulating DHEA levels to at least 15 nmol/L. Secondary objectives are to assess if DHEA supplementation has any effect on neutrophil function, metabolic and cytokine profiles and which route of administration (oral vs sublingual) is more effective in restoring circulating levels of DHEA, DHEAS and downstream androgens. METHODS AND ANALYSIS: A prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its profile in trauma, with a planned recruitment between April 2019 and July 2021, that will investigate DHEA supplementation and its effect on serum DHEA, DHEAS and downstream androgens in trauma. A maximum of 270 patients will receive sublingual or oral DHEA at 50, 100 or 200 mg daily over 3 days. Females aged ≥50 years with neck of femur fracture and male and female major trauma patients, aged 16-50 years with an injury severity score ≥16, will be recruited. ETHICS AND DISSEMINATION: This protocol was approved by the West Midlands - Coventry and Warwickshire Research Ethics Committee (Reference 18/WM/0102) on 8 June 2018. Results will be disseminated via peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION: This trial is registered with the European Medicines Agency (EudraCT: 2016-004250-15) and ISRCTN (12961998). It has also been adopted on the National Institute of Health Research portfolio (CPMS ID:38158). TRIAL PROGRESSION: The study recruited its first patient on 2 April 2019 and held its first data monitoring committee on 8 November 2019. DHEA dosing has increased to 100 mg in both male cohorts and remains on 50 mg in across all female groups.

Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer.

BACKGROUND: The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. METHODS: We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. RESULTS: We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. CONCLUSIONS: Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.