scholarly journals A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

2021 ◽  
Vol 25 (4) ◽  
pp. 305-314
Author(s):  
C. D. Tweed ◽  
G. H. Wills ◽  
A. M. Crook ◽  
E. Amukoye ◽  
V. Balanag ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Randomised Trial ◽  
Group Differences ◽  
Pulmonary Tb ◽  
Intention To Treat ◽  
Tb Treatment ◽  
Grade 3 ◽  
To Receive ◽  
Ongoing Evaluation ◽  
Post Randomisation

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

scholarly journals Evaluating a Values-Based Intervention for Adolescence with High Nonclinical Paranoia: A Schools-Based Randomised Control Trial

2021 ◽  
Author(s):  
A. Parker ◽  
J. Kingston
Keyword(s):  
Active Control ◽  
Primary Outcome ◽  
Randomised Trial ◽  
Self Esteem ◽  
Randomised Control Trial ◽  
Intention To Treat ◽  
Low Intensity ◽  
Time Interaction ◽  
Potential Mediator

Abstract Background Paranoia in adolescents is common, but research on attenuating it is scarce. Focusing on values and enhancing value-based acts is a low intensity method for attenuating paranoia in adults. This randomised trial compared a brief (30-min, self-directed) values-plus-goals intervention to an active control for adolescents with high nonclinical paranoia (Paranoia Scale ≥ 53), delivered in schools. The study also investigated the role of self-esteem. Methods Ninety adolescents were randomly assigned to condition. Paranoia (primary outcome) and self-esteem (potential mediator) were assessed at baseline (T1), and two- (T2) and six-weeks (T3) after baseline. Results Results were analysed using intention to treat (ITT) and per protocol (PP) analysis. Using ITT analysis, the Condition*Time interaction was significant (F(2, 168) = 3.98, p = .02), paranoia was significantly lower at T3 following values-plus-goals as compared to control (d = 0.64). Differences were not significant using per protocol analysis (F(2, 106) = 1.61, p = .21). The between group effect size at T3 was (d = 0.61). The Condition*Time interaction for self-esteem was not significant (F(2, 112) = 2.86, p = .06). Conclusions Tentatively, findings suggest that a brief values-plus-goals intervention can reduce paranoia in adolescents relative to an active control.

scholarly journals Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
P. P. J. Phillips ◽  
A. Van Deun ◽  
S. Ahmed ◽  
R. L. Goodall ◽  
S. K. Meredith ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Informative Censoring ◽  
Sensitivity Analyses ◽  
Cumulative Number ◽  
Loss To Follow Up ◽  
Intention To Treat ◽  
Resistant Tuberculosis ◽  
Future Drug ◽  
Grade 3 ◽  
The Impact

Abstract Background The STREAM trial demonstrated that a 9–11-month “short” regimen had non-inferior efficacy and comparable safety to a 20+ month “long” regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. Methods Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. Results Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3–4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. Conclusion Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

scholarly journals Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial

RMD Open ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. e001047 ◽  
Author(s):  
Emilie Ducourau ◽  
Theo Rispens ◽  
Marine Samain ◽  
Emmanuelle Dernis ◽  
Fabienne Le Guilchard ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Primary Outcome ◽  
Axial Spondyloarthritis ◽  
Randomised Trial ◽  
Follow Up Study ◽  
Study Completion ◽  
To Receive ◽  
Term Maintenance

ObjectivesAnti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.MethodsA total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX−). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration.ResultsWe analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX− group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX− group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04).ConclusionMTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.

Gemcitabine and cisplatin (GP) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC): A phase 3, multicenter, randomized controlled trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6003-6003 ◽  
Author(s):  
Jun Ma ◽  
Yuan Zhang ◽  
Ying Sun ◽  
Fangyun Xie ◽  
Weihan Hu ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Intensity Modulated Radiotherapy ◽  
Free Survival ◽  
Intention To Treat ◽  
Multicenter Randomized Controlled Trial ◽  
Common Grade ◽  
Grade 3 ◽  
To Receive ◽  
Treat Population

6003 Background: GP regimen has been established as the standard first-line treatment option for patients with recurrent/metastatic NPC. However, its efficacy in locoregionally advanced disease remains unclear. Methods: Patients with previously untreated, non-metastatic stage III-IVB (except T3-4N0M0, AJCC 7th) NPC, aged 18–64 years without severe comorbidities were eligible. They were randomly assigned (1:1) to receive GP IC (gemcitabine 1 g/m2on days 1 & 8, cisplatin 80 mg/m2 on day 1, q3w for 3 cycles) plus CCRT (cisplatin 100 mg/m2, q3w for 3 cycles, concurrently with intensity-modulated radiotherapy) or CCRT alone. The primary endpoint was failure-free survival (FFS). The calculated sample size was 238 per group, with an 80% power (two-sided α 0.05) to detect a treatment failure hazard ratio (HR) of 0.52. Results: From Dec 2013 to Sep 2016, 480 patients from 12 centers were randomly assigned to IC+CCRT (n = 242) or CCRT alone (n = 238) group. Baseline characteristics were well balanced. After a median follow-up of 39 months, 3-year FFS was 85.8% in the IC+CCRT group and 77.2% in the CCRT alone group (intention-to-treat population; HR 0.53, 95% confidence interval 0.34–0.81; P = 0.003). In GP+CCRT group, 239 patients started GP IC and 231 (96.7%) completed all three cycles. The most common ≥grade 3 adverse events (AE) in IC+CCRT and CCRT group were mucositis (28.9% vs. 32.1%), neutropenia (28.0% vs. 10.5%) and leukopenia (26.4% vs. 20.3%). Conclusions: Adding GP IC to CCRT significantly improved FFS in locoregionally advanced NPC and is well tolerated with favorable toxicity profile. Clinical trial information: NCT01872962. [Table: see text]

Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial

Blood ◽  
2022 ◽  
Author(s):  
Yi Ji ◽  
Siyuan Chen ◽  
Jiangyuan Zhou ◽  
Kaiying Yang ◽  
Xuepeng Zhang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Outcome ◽  
Treatment Strategies ◽  
Platelet Response ◽  
Kaposiform Hemangioendothelioma ◽  
Total Incidence ◽  
Short Course ◽  
Life Threatening ◽  
Grade 3 ◽  
To Receive

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone versus sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100×109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% CI, 10.0% to 44.7%). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment for KHE with KMP. ClinicalTrial.gov, number NCT03188068

scholarly journals Short email with attachment versus long email without attachment when contacting authors to request unpublished data for a systematic review: a nested randomised trial

BMJ Open ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. e025273 ◽  
Author(s):  
Peter J Godolphin ◽  
Philip M Bath ◽  
Alan A Montgomery
Keyword(s):  
Systematic Review ◽  
Primary Outcome ◽  
Additional Data ◽  
Response Rate ◽  
Randomised Trial ◽  
Secondary Outcome ◽  
Unit Of Analysis ◽  
Secondary Outcomes ◽  
To Receive ◽  
Contacting Authors

ObjectiveSystematic reviews often rely on the acquisition of unpublished analyses or data. We carried out a nested randomised trial comparing two different approaches for contacting authors to request additional data for a systematic review.ParticipantsParticipants were authors of published reports of prevention or treatment trials in stroke in which there was central adjudication of events. A primary and secondary research active author were selected as contacts for each trial.InterventionsAuthors were randomised to be sent either a short email with a protocol of the systematic review attached (‘Short’) or a longer email that contained detailed information and without the protocol attached (‘Long’). A maximum of two emails were sent to each author to obtain a response. The unit of analysis was trial, accounting for clustering by author.Primary and secondary outcome measuresThe primary outcome was whether a response was received from authors. Secondary outcomes included time to response, number of reminders needed before a response was received and whether authors agreed to collaborate.Results88 trials with 76 primary authors were identified in the systematic review, and of these, 36 authors were randomised to Short (trials=45) and 40 to Long (trials=43). Responses were received for 69 trials. There was no evidence of a difference in response rate between trial arms (Short vs Long, OR 1.10, 95% CI 0.36 to 3.33). There was no evidence of a difference in time to response between trial arms (Short vs Long, HR 0.91, 95% CI 0.55 to 1.51). In total, 27% of authors responded within a day and 22% of authors never responded.ConclusionsThere was no evidence to suggest that email format had an impact on the number of responses received when acquiring data for a systematic review involving stroke trials or the time taken to receive these responses.

scholarly journals The effect of multi-vitamin/mineral supplementation on mortality during treatment of pulmonary tuberculosis: a randomised two-by-two factorial trial in Mwanza, Tanzania

2006 ◽  
Vol 95 (4) ◽  
pp. 762-770 ◽  
Author(s):  
Nyagosya Range ◽  
John Changalucha ◽  
Henrik Krarup ◽  
Pascal Magnussen ◽  
Âse B. Andersen ◽  
...  
Keyword(s):  
Weight Gain ◽  
Pulmonary Tuberculosis ◽  
Randomised Trial ◽  
Pulmonary Tb ◽  
Survival Status ◽  
Tb Treatment ◽  
Mineral Supplementation ◽  
Supplementation Period ◽  
Factorial Trial ◽  
Combined Intervention

Malnutrition is common in pulmonary tuberculosis (TB), and may impair survival. The objective of this study was to assess effects of multi-vitamin/mineral (MVM) and zinc (Zn) supplementation during TB treatment on mortality. Patients diagnosed with sputum-positive pulmonary TB in Mwanza, Tanzania, were randomised, using a two-by-two factorial design, to Zn (45mg) or placebo, and MVM (vitamins A, B, C, D, E, and selenium and copper) or placebo. Survival status was ascertained at the end of the 8-month TB treatment and supplementation period. Of 499 TB patients, 213 (43%) had HIV. The mean weight gain at 7 months was 6·88kg (95% CI 6·36, 7·41). Zn and MVM combined, but neither alone (interaction, p=0·03), increased weight gain by 2·37kg (95% CI 0·91, 3·83), irrespective of HIV status. Survival status at 8 months was determined for 422 patients (84·6%), of which fifty-two (12·3%) had died. Among fifty-two deaths, there were no effects of MVM (relative risk (RR) 0·73; 95% CI 0·43, 1·23) and Zn (RR 0·76; 95% CI 0·46, 1·28). However, among HIV co-infected patients, marginally significant effects of both MVM (RR 0·60; 95% CI 0·34, 1·05) and Zn (RR 0·63, 95% CI 0·37, 1·08) were seen, and MVM and Zn combined reduced mortality (RR 0·29; 95% CI 0·10, 0·80; interaction ratio 0·52). In conclusion, supplementation with MVM, including Zn, during treatment of pulmonary TB may reduce mortality in those co-infected with HIV. A randomised trial of the effect of the combined intervention used in this study should be conducted in a different setting to confirm the finding.

scholarly journals A nested randomised trial of the effect of tranexamic acid on intracranial haemorrhage and infarction in traumatic brain injury (CRASH-3 trial intracranial bleeding mechanistic study): Statistical analysis plan

2019 ◽  
Vol 3 ◽  
pp. 99
Author(s):  
Abda Mahmood ◽  
Ian Roberts ◽  
Haleema Shakur-Still
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Primary Outcome ◽  
Randomised Trial ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Mechanistic Study ◽  
Cerebral Infarcts ◽  
Post Randomisation

Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) on death and disability in traumatic brain injury (TBI). The CRASH-3 intracranial bleeding mechanistic study (IBMS) is a randomised trial nested within the CRASH-3 trial to examine the effect of TXA on intracranial bleeding and infarction. Methods: Patients eligible for the CRASH-3 trial, with a GCS of 12 or less or intracranial bleeding on a pre-randomisation CT scan are eligible for the IBMS. The occurrence of intracranial bleeding, infarction, haemorrhagic oedematous lesions, mass effect and haemorrhage evacuation is examined within 28 days of randomisation using routinely collected brain scans. The primary outcome is the volume of intra-parenchymal bleeding in patients randomised within three hours of injury (adjusted for prognostic covariates). Secondary outcomes include a composite “poor” outcome, progressive and new intracranial bleeding, intracranial bleeding after neurosurgery and cerebral infarcts seen up to 28 days post-randomisation. All outcomes will be compared between treatment groups. Statistical analyses: The primary outcome will be analysed using a covariate adjusted linear mixed model. The same analysis will be done separately for patients who undergo haemorrhage evacuation post-randomisation. We will express the effect of TXA on the composite outcome, new and progressive bleeding using relative risks and 95% CIs, and on cerebral infarcts using hazard ratios and 95% CIs. We will conduct sensitivity analyses assuming missing data are MCAR or MNAR. Conclusion: The IBMS will provide information on the mechanism of action of TXA in TBI. This pre-specified statistical analysis plan is a technical extension of the published protocol. Trial registration: The CRASH-3 trial was prospectively registered at the International Standard Randomised Controlled Trials registry (19 July 2011) and ClinicalTrials.gov (25 July 2011). The registries were updated with details for the IBMS on 20 December 2016.

scholarly journals Evaluation of implementation and effectiveness of digital adherence technology with differentiated care to support tuberculosis treatment adherence and improve treatment outcomes in Ethiopia: a study protocol for a cluster randomised trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Amare W. Tadesse ◽  
Zemedu Mohammed ◽  
Nicola Foster ◽  
Matthew Quaife ◽  
Christopher Finn McQuaid ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Patient Adherence ◽  
Randomised Trial ◽  
Standard Of Care ◽  
Cluster Randomised Trial ◽  
Pulmonary Tb ◽  
Tb Treatment ◽  
Cluster Randomised ◽  
End Of Treatment ◽  
Differentiated Care

Abstract Background Digital adherence technologies (DATs) are recommended to support patient-centred, differentiated care to improve tuberculosis (TB) treatment outcomes, but evidence that such technologies improve adherence is limited. We aim to implement and evaluate the effectiveness of smart pillboxes and medication labels linked to an adherence data platform, to create a differentiated care response to patient adherence and improve TB care among adult pulmonary TB participants. Our study is part of the Adherence Support Coalition to End TB (ASCENT) project in Ethiopia. Methods/Design We will conduct a pragmatic three-arm cluster-randomised trial with 78 health facilities in two regions in Ethiopia. Facilities are randomised (1:1:1) to either of the two intervention arms or standard of care. Adults aged ≥ 18 years with drug-sensitive (DS) pulmonary TB are enrolled over 12 months and followed-up for 12 months after treatment initiation. Participants in facilities randomised to either of the two intervention arms are offered a DAT linked to the web-based ASCENT adherence platform for daily adherence monitoring and differentiated response to patient adherence for those who have missed doses. Participants at standard of care facilities receive routine care. For those that had bacteriologically confirmed TB at treatment initiation and can produce sputum without induction, sputum culture will be performed approximately 6 months after the end of treatment to measure disease recurrence. The primary endpoint is a composite unfavourable outcome measured over 12 months from TB treatment initiation defined as either poor end of treatment outcome (lost to follow-up, death, or treatment failure) or treatment recurrence measured 6 months after the scheduled end of treatment. This study will also evaluate the effectiveness, feasibility, and cost-effectiveness of DAT systems for DS-TB patients. Discussion This trial will evaluate the impact and contextual factors of medication label and smart pillbox with a differentiated response to patient care, among adult pulmonary DS-TB participants in Ethiopia. If successful, this evaluation will generate valuable evidence via a shared evaluation framework for optimal use and scale-up. Trial registration: Pan African Clinical Trials Registry PACTR202008776694999, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241, registered on August 11, 2020.

scholarly journals Efficacy of Chlorhexidine Varnish for the Prevention of Adult Caries

2011 ◽  
Vol 91 (2) ◽  
pp. 150-155 ◽  
Author(s):  
A.S. Papas ◽  
W.M. Vollmer ◽  
C.M. Gullion ◽  
J. Bader ◽  
R. Laws ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Tooth Surface ◽  
Placebo Control ◽  
Double Blind ◽  
Intention To Treat ◽  
Significant Difference ◽  
Registration Number ◽  
Secondary Outcomes ◽  
Study Participants ◽  
To Receive

The Prevention of Adult Caries Study, an NIDCR-funded multicenter, double-blind, randomized clinical trial, enrolled 983 adults (aged 18-80 yrs) at high risk for developing caries (20 or more intact teeth and 2 or more lesions at screening) to test the efficacy of a chlorhexidine diacetate 10% weight per volume (w/v) dental coating (CHX). We excluded participants for whom the study treatment was contraindicated or whose health might affect outcomes or ability to complete the study. Participants were randomly assigned to receive either the CHX coating (n = 490) or a placebo control (n = 493). Coatings were applied weekly for 4 weeks and a fifth time 6 months later. The primary outcome (total net D1-2FS increment) was the sum of weighted counts of changes in tooth surface status over 13 months. We observed no significant difference between the two treatment arms in either the intention-to-treat or per-protocol analyses. Analysis of 3 protocol-specified secondary outcomes produced similar findings. This trial failed to find that 10% (w/v) chlorhexidine diacetate coating was superior to placebo coating for the prevention of new caries ( Clinicaltrials.gov registration number NCT00357877).

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