Lanreotide versus placebo for tumour reduction in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma (GALANT study): a randomised, multicentre, phase 3 trial with blinded outcome assessment.

Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.

Comparative effect of electroacupuncture with different frequency on headache attacks in migraine outpatients: study protocol for a randomised placebo-controlled trial.

BACKGROUND: Headache attacks severely impaired life quality and increase the economic burden of migraineurs. Electroacupuncture (EA) has been used worldwidely to treat several pain-related diseases including migraines. However, whether EA with low or high frequency exerts a distinct analgesic effect remains unknown and needs further study. METHODS/DESIGN: This study is a randomised, single-blinded, placebo-controlled trial with three parallel arms. A total of 144 migraine outpatients will be randomly allocated to the 2 Hz EA group, 100 Hz EA group and placebo control group. The duration of the trial is 20 weeks, including a 4-week-long baseline assessment period (weeks - 4-0), a 4-week-long treatment period (weeks 1-4) and a 12-week-long follow-up period (weeks 5-16). Twelve treatment sessions will be performed over a 4-week period (weeks 1-4). The primary outcome will be measured by the frequency of migraine attacks in the past 4 weeks at the end of week 4 post-randomisation. The secondary outcome will be measured by the frequency of migraine attacks in the past 4 weeks at the end of weeks 8, 12 and16 post-randomisation; number of days with migraine; dosage of ibuprofen; the scores of visual analogue scale (VAS); Self-Rating Anxiety Scale (SAS); Self-Rating Depression Scale (SDS); and Migraine Specific Quality of Life questionnaire (MSQ) in the past 4 weeks at the end of weeks 4, 8, 12 and 16 post-randomisation. Safety assessment, compliance and blinding evaluation will be carried out at the end of week 16 post-randomisation. DISCUSSION: The recruitment will be started on 1 June 2021 and expected to finish on 31 May 2023. We aimed to clarify the dominant frequency of EA on headache attacks in a migraineur. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-1800017259 . Registered on 20 July 2018.

A randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the efficacy and safety of SARS-CoV-2 vaccine (inactivated, Vero cell): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective is to evaluate the efficacy of an inactivated and aluminium hydroxide adsorbed SARS-CoV-2 vaccine (Sinovac, China) in voluntary participants after 14 days of the second dose against RT-PCR confirmed symptomatic COVID-19 cases. The secondary objectives include evaluating the efficacy after at least one dose of the vaccine against RT-PCR confirmed symptomatic COVID-19 cases; the efficacy of two doses of the vaccine on the rates of hospitalization and death; the safety of the vaccine including adverse reactions up to one year after the 2nd dose of vaccination; and the immunogenicity of the vaccine and its duration up to 120 days. TRIAL DESIGN: This is a phase III, randomized, double-blind, placebo-controlled case driven clinical trial to assess the efficacy and safety of the vaccine. The study is planned to be carried out within two separate cohorts in voluntary participants aged between 18-59 years old. The first cohort includes healthcare professionals actively working in healthcare units, who are assumed to have higher risk of acquiring COVID-19, and the second cohort includes other immunocompetent subjects in the same age group, who are at a regular risk for COVID-19 disease. In Cohort 1, healthcare professionals will be randomized to receive two intramuscular doses of investigational product or the placebo in a 1:1 ratio and they will be monitored for 12 months by active surveillance of COVID-19. In Cohort 2, immunocompetent subjects will be randomized to receive vaccine or the placebo in a 2:1 ratio. PARTICIPANTS: Healthcare professionals of both genders, including medical doctors, nurses, cleaners, hospital technicians, and administrative personnel who work in any department of a healthcare unit and immunocompetent individuals of both genders are included. Pregnant (confirmed by positive beta-hCG test) and breastfeeding women as well as those intending to become pregnant within three months after vaccination are excluded. Other exclusion criteria include history of COVID-19 test positivity (PCR or immunoglobulin test results), any form of immunosuppressive therapy including corticosteroids within 6 months, history of bleeding disorders, asplenia, and administration of any form of immunoglobulins or blood products within 3 months. Exclusion criteria for the second dose include any serious adverse events related with the vaccine, anaphylaxis or hypersensitivity after vaccination, or any confirmed or suspected autoimmune or immunosuppressive disease (including HIV infection). Participants are only included after signing the voluntary informed consent form, ensuring cooperation in visits, undergoing screening for evaluation, and conforming to all the inclusion and exclusion criteria. All clinical sites are located in Turkey. INTERVENTION AND COMPARATOR: The vaccine was manufactured by Sinovac Research & Development Co., Ltd. It is a preparation made from a novel coronavirus (strain CZ02) grown in the kidney cell cultures (Vero Cell) of the African green monkey and contains inactivated SARS-CoV-2 virus, aluminium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride. A dose of 0.5 mL contains 600 SU of SARS-CoV-2 virus antigen. The placebo contains aluminium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride (0.5mL/dose). Scheduled visits and additional unscheduled weekly visits will be performed for the first 13 weeks and neutralizing antibody test, IgG test, T-Cell activation test, pregnancy test, and RT-PCR tests along with total antibody test will be performed. Adverse events and serious adverse events during the follow-up will be recorded on diary cards. Diary cards will collect information on the timing and severity of COVID-19 symptoms and solicited adverse events recorded by the subjects during one-year follow-up period. All serious adverse events will be managed and necessary treatment will be ensured according to the local regulations. All serious adverse events following vaccination will be reported to the ethics committee, the Ministry of Health, and the study sponsor within 24 hours of detection. MAIN OUTCOMES: The primary efficacy endpoint is the incidence of symptomatic cases of COVID-19 disease confirmed by RT-PCR two weeks after the second dose of vaccination. Secondary efficacy endpoints are the incidence of hospitalization/mortality rates among one or two dose regimens, duration of immunogenicity rates up to 120 days, the seroconversion rate, the seropositivity rate, neutralizing antibody titer, and IgG levels 14 days after each dose of vaccination. The primary safety endpoint is the severity and frequency of local and systemic adverse reactions during the period of one week after vaccination. The study would be terminated if more than 15% of the subjects have grade ≥3 adverse events related to vaccination including local reactions. RANDOMISATION: Eligible subjects will be randomized at their Study Day 0 to two study groups using an Interactive Web Response System (IWRS; developed by Omega CRO, Ankara, Turkey) in both risk groups. The IWRS system customizes the randomization algorithm. After enrolment in the study, each participant will be randomly assigned to either of the two treatment arms at a ratio of 1:1 in the high-risk group and at a ratio of 2:1 in the normal risk group. Each enrolled participant will be assigned to a code and will receive the treatment labelled with the code. BLINDING (MASKING): The trial is a double-blind study to avoid introducing bias. The blinding may be broken by the investigator in the event of a medical emergency in which knowledge of the identity of the study vaccine is critical for management of the subject's immediate treatment. The Data and Safety Monitoring Board is to be contacted in case of breaking the blinding for a study object. The blood samples will be taken from both placebo and vaccinated groups, in order not to break the blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study is planned to be carried out with two separate cohorts. The Cohort 1 includes healthcare professionals working in healthcare units and the Cohort 2 consists of immunocompetent subjects having normal risk for COVID-19 disease. The Cohort 2 will be initiated after the evaluation of the interim safety report of the Cohort 1 by the Data and Safety Monitoring Board. Both cohorts will be followed-up via RT-PCR to confirm symptomatic COVID-19 cases. If the clinical efficacy of the vaccine is shown in the Cohort 1 or 2, the subjects randomized into the placebo arm will also be vaccinated. In the Cohort 1, 588 subjects should be included in both arms with the assumption that the risk of infection with COVID-19 will be 5% for the placebo arm and 2% for the vaccine arm in the high-risk group. Considering 10% of drop-out rate and 5% of seropositivity or PCR positivity at baseline, 680 subjects should be screened at both arms of the Cohort 1. Group sample sizes of 7545 SARS-CoV-2 vaccine and 3773 placebo suits at a two-sided 95% confidence interval for the difference in population proportions with a width equal to 1.0%, when the estimated incidence rate for vaccinated group is 1.0% and the estimated incidence rate for placebo group is 2.0%. Drop-out rate is assumed to be 10% and seropositivity or PCR positivity at baseline is assumed to be 5%; accordingly, 13000 participants are needed to be enrolled totally in both cohorts. The remaining 11640 subjects will be screened in the Cohort 2 and eligible subjects will be randomized at a ratio of 2:1. TRIAL STATUS: Protocol version 6.0 - 15 October 2020. Recruitment started on 15.09.2020 and is expected to end on February 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04582344 . Registered 8 October 2020 FULL PROTOCOL: The full protocol of the trial 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.

Protecting Frontline Health Care Workers from COVID-19 with Hydroxychloroquine Pre-exposure Prophylaxis: A structured summary of a study protocol for a randomised placebo-controlled multisite trial in Toronto, Canada.

OBJECTIVES: Primary Objective: To determine if pre-exposure prophylaxis (PrEP) with 400mg hydroxychloroquine (HCQ), taken orally once daily reduces microbiologically confirmed COVID-19 among front line health care workers at high risk for SARS-CoV-2 exposure. Secondary Objectives: To compare the following between study arms: adverse events; symptomatic COVID-19; duration of symptomatic COVID-19; days hospitalized attributed to COVID-19; respiratory failure attributable to COVID-19 requiring i) non-invasive ventilation or ii) intubation/mechanical ventilation; mortality attributed to COVID-19, number of days unable to work attributed to COVID-19, seroconversion (COVID-19 negative to COVID-19 positive over the study period); ability of participant plasma to neutralize SARS-CoV-2 virus in vitro; To describe short-term psychological distress associated with risk of COVID-19 exposure at 1, 60, 120 days of the study. To explore laboratory markers within participants with confirmed COVID-19: including circulating markers of host immune and endothelial activation in participant plasma and their correlation with disease severity and outcome TRIAL DESIGN: The HEROS study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), placebo controlled, participant and investigator-blinded, multi-site superiority trial of oral HCQ 400 mg taken once daily for 90 days as PrEP to prevent COVID-19 in health care workers at high risk of SARS-CoV-2 exposure. At 90 days, there is an open label extension wherein all participants are offered a one-month course of HCQ 400mg once daily for PrEP of COVID-19. PARTICIPANTS: Frontline HCWs aged 18 years of age or older, at high risk of SARS-CoV-2 exposure (including staff of emergency departments, intensive care units, intubation teams, COVID-wards, and staff deployed to Long Term Care facilities) of five academic hospitals in downtown Toronto, Canada. Exclusion criteria include: currently pregnant, planning to become pregnant during the study period, and/or breast feeding; known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds; current use of hydroxychloroquine; known prolonged QT syndrome and/or baseline resting ECG with QTc>450 ms and/or concomitant medications which simultaneously may prolong the QTc that cannot be temporarily suspended/replaced; known pre-existing retinopathy, G6PD deficiency, porphyria, liver disease including cirrhosis, encephalopathy, hepatitis or alcoholism, diabetes on oral hypoglycemics or insulin, or renal insufficiency/failure; disclosure of self-administered use of hydroxychloroquine or chloroquine within 12 weeks prior to study; confirmed symptomatic COVID-19 at time of enrollment. INTERVENTION AND COMPARATOR: Intervention: hydroxychloroquine, 400mg (2 tablets) orally per day. Comparator: placebo, two tablets visually identical to the intervention, orally per day MAIN OUTCOMES: The primary outcome is microbiologically confirmed COVID-19 (i.e. SARS-CoV-2 infection). This is a composite endpoint which includes positive results from any validated SARS-CoV-2 diagnostic assay including detection of viral RNA, and/or seroconversion. Participants will be assessed at baseline, and then undergo monthly follow-up at day 30, 60, and 90, 120. At each visit, participants will provide an oropharyngeal sample, blood sample, and will undergo electrocardiogram monitoring of the QTc interval. Secondary outcome measures include: adverse events; symptom duration of COVID-19; days of hospitalization attributed to COVID-19; respiratory failure requiring ventilator support attributed to COVID-19; mortality attributed to COVID-19; total days off work attributed to COVID-19; seropositivity (reactive serology by day 120); and short term psychological impact of exposure to SARS-CoV-2 at day 1, 60, 120 days using the K10, a validated measure of non-specific psychological distress. RANDOMISATION: Within each site, participants will be individually randomized to either the intervention arm with HCQ or the placebo arm using a fixed 1:1 allocation ratio using an interactive web-based response system to ensure concealment of allocation. Randomization schedules will be computer-generated and blocked using variable block sizes. BLINDING (MASKING): All participants, research coordinators, technicians, clinicians and investigators will be blinded to the participant allocation group. Numbers to be randomised (sample size) N=988, randomised into two groups of 494 patients. TRIAL STATUS: This summary describes protocol version No. 1.6, May 15, 2020. Recruitment is ongoing - started April 20, 2020 and anticipated end date is July 30, 2021 TRIAL REGISTRATION: ISRCTN.com Identifier: ISRCTN14326006, registered April 14, 2020. 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 (Additional file 2).

Detailed statistical analysis plan for the Dutch STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset fetal growth Restriction) randomised clinical trial on sildenafil versus placebo for pregnant women with severe early onset fetal growth restriction.

OBJECTIVE: The objective of the Dutch Sildenafil therapy in dismal prognosis early onset fetal growth restriction (STRIDER) randomised clinical trial is to assess the beneficial and harmful effects of sildenafil versus placebo on fetal and neonatal mortality in pregnant women with severe early-onset fetal growth restriction. The objective of this detailed statistical analysis plan is to minimize the risks of selective reporting and data-driven analysis. SETTING: The setting is 10 tertiary care hospitals and one secondary care hospital in The Netherlands. PARTICIPANTS: The participants will be 360 pregnant women with severe early-onset fetal growth restriction. INTERVENTIONS: The intervention is sildenafil 25 mg or placebo orally three times a day. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is a composite of death or major neonatal morbidity assessed at hospital discharge. The secondary outcomes are neurodevelopmental impairment; mean scores of the Bayley III cognitive and motor assessment; the proportion of patients experiencing either preeclampsia or haemolysis, elevated liver enzymes, and low platelets syndrome; pulsatility index of uterine arteries, umbilical artery, and middle cerebral artery; birthweight; and gestational age at either delivery or intra-uterine death. RESULTS: A detailed statistical analysis is presented, including pre-defined exploratory outcomes and planned subgroup analyses. One interim analysis after 180 patients had completed the study was planned and a strategy to minimise the risks of type I errors due to repetitive testing is presented. During review of this manuscript the interim analysis was performed by the Data Safety Monitoring Board and early stopping of the trial was recommended. Final analyses will be conducted independently by two statistically qualified persons following the present plan. CONCLUSION: This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data and updated after stopping of the trial at interim analysis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02277132 . Registered on 29 September 2014. Original protocol for the study: doi: https://doi.org/10.5281/zenodo.56148.

STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials.

BACKGROUND: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis. METHODS: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation. DISCUSSION: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis. TRIAL REGISTRATIONS: New Zealand and Australia: ACTRN12612000584831 . Registered 30/05/2012. Canada: NCT02442492 . Registered 05/05/2015. Ireland: CT 900/572/1 . Registered 15/07/2015. The Netherlands: NCT02277132 . Registered 29/09/2014. United Kingdom: ISRCTN39133303 . Registered 31/07/2014.

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ2=0.41; p=0.813) or the 16-weeks complete medication period (χ2=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

Randomised, double-blind, placebo-controlled, cross-over single dose study of the bronchodilator duration of action of combination fluticasone furoate/vilanterol inhaler in adult asthma.

BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a once-daily maintenance treatment for asthma and chronic obstructive pulmonary disease. The duration of bronchodilation beyond 24 h has not been determined previously. METHODS: Adults aged 18-65 (n = 32), with asthma and reversibility to salbutamol (≥15% and ≥200 mL increase in forced expiratory volume in 1 s [FEV1]) participated in a double-blind, placebo-controlled, crossover study. Patients were admitted to a clinical trials unit for 72 h, and inhaled, in random order, placebo or FF/VI 100/25 mcg via ELLIPTA dry powder inhaler on two occasions 7-14 days apart. FEV1 was measured at baseline, 15 and 30 min, 1, 2, 4, 12, 24, 36, 48, 60, and 72 h. The differences in change in FEV1 from baseline between treatments and corresponding two-sided 95% confidence intervals (CI) were calculated at each time point. FINDINGS: FF/VI produced a rapid onset of bronchodilation (adjusted mean difference in change from baseline in FEV1 versus placebo at 15 min, 252 mL [95% CI 182-322]). Maximum bronchodilation was observed at 12 h (adjusted mean difference in the change from baseline in FEV1, 383 mL [95% CI 285-481]). Bronchodilation was maintained throughout the 72-h assessment period (adjusted mean difference in the change in FEV1 from baseline at 72 h, 108 mL (95% CI 15-200]). FF/VI was well tolerated and no serious side effects were reported. INTERPRETATION: A single dose of FF/VI 100/25 mcg showed evidence of a 72-h bronchodilator duration of action in adults with asthma.

The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial.

OBJECTIVE: Epidemiological data suggest low serum 25-hydroxyvitamin D3 (25-OH-D3) levels are associated with radiological progression of knee osteoarthritis (OA). This study aimed to assess whether vitamin D supplementation can slow the rate of progression. METHOD: A 3-year, double-blind, randomised, placebo-controlled trial of 474 patients aged over 50 with radiographically evident knee OA comparing 800 IU cholecalciferol daily with placebo. Primary outcome was difference in rate of medial joint space narrowing (JSN). Secondary outcomes included lateral JSN, Kellgren & Lawrence grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, stiffness and the Get up and Go test. RESULTS: Vitamin D supplementation increased 25-OH-D3 from an average of 20.7 (standard deviation (SD) 8.9) µg/L to 30.4 (SD 7.7) µg/L, compared to 20.7 (SD 8.1) µg/L and 20.3 (SD 8.1) µg/L in the placebo group. There was no significant difference in the rate of JSN over 3 years in the medial compartment of the index knee between the treatment group (average -0.01 mm/year) and placebo group (-0.08 mm/year), average difference 0.08 mm/year (95% confidence interval (CI) [-0.14-0.29], P = 0.49). No significant interaction was found between baseline vitamin D levels and treatment effect. There were no significant differences for any of the secondary outcome measures. CONCLUSION: Vitamin D supplementation did not slow the rate of JSN or lead to reduced pain, stiffness or functional loss over a 3-year period. On the basis of these findings we consider that vitamin D supplementation has no role in the management of knee OA.

Neurofeedback ineffective in paediatric brain tumour survivors: Results of a double-blind randomised placebo-controlled trial.

BACKGROUND: Many paediatric brain tumour survivors (PBTS) suffer from neurocognitive impairments. Promising effects of neurofeedback (NF) on neurocognitive functioning have been reported, however research into NF for PBTS has not been conducted. We investigated the effects of NF on neurocognitive functioning in PBTS using a double-blind randomised placebo-controlled trial with a parallel-group design (Pediatric Research on Improving Speed, Memory, and Attention; the PRISMA study). METHODS: Eligible for inclusion were PBTS with neurocognitive complaints, aged 8-18 years, >2 years post-treatment. They were recruited from five medical centres in the Netherlands. A randomisation table assigned participants to 30 sessions (two per week) of either NF or placebo feedback (PF) (ratio 1:1). Participants, parents, trainers, and researchers handling the data were blinded to group assignment. Participants were assessed pre-, post- and 6 months post-training to determine whether NF training would lead to improved functioning as compared with PF training. Primary outcome measures were attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence. Linear mixed models analyses were used to test differences between NF and PF training over time. RESULTS: A total of 82 children were enrolled (mean age 13.9 years, standard deviation = 3.2, 49% males); 80 participants were randomised (NF: n = 40, PF n = 40); 71 participants completed the training (NF: n = 34, PF: n = 37); 68 participants completed training and 6 months post-training assessment (NF: n = 33, PF: n = 35). Similar improvements were found over time for the two treatment groups on the primary outcomes (all p's > 0.15). CONCLUSION: Results indicated no specific treatment-effects of NF on neurocognitive functioning of PBTS.

Temporary sympathectomy in chronic refractory angina: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Temporary sympathectomy by injection of bupivacaine at the site of the left stellate ganglion is used in the management of refractory angina at several UK centres. Although patients frequently report significant reduction in symptoms, efficacy has not been established by double-blind, randomised placebo-controlled trial (RCT). OBJECTIVE: To investigate the efficacy of the procedure for the first time by a double-blind RCT. METHODS: Consecutive patients referred to the authors' National Health Service (NHS) angina centre who were candidates for temporary sympathectomy were invited to participate in a trial. A total of 65 patients were randomised to receive either bupivacaine or saline injections. Identical syringes were prepared remotely, blinding patients and staff from randomisation. Cardiac autonomic function was measured 3 hours pre- and post-injection using new heart rate variability (HRV) analyses. Angina episodes were recorded contemporaneously by patients in study diaries in the 7-day periods pre- and post-injection. RESULTS: In 51 patients suitable for analysis, no significant differences between the active and placebo groups were found in patient-recorded frequency or intensity of angina episodes pre- and post-injection. However, across both groups combined, a significant difference was found in the frequency of angina episodes pre- and post-injection. CONCLUSION: The reduction in frequency of angina episodes produced by this procedure may not be due to drug pharmacology. It may be a placebo response or due to the mechanical effects of the injection of fluid. There is a need for further work using a larger patient cohort considering both mechanical and psychological factors.