MoreTrials

MoreTrials: A public campaign to make it much easier to do randomised trials

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MoreTrials welcomes new supporters!

MoreTrials welcomes the following patient groups and medical societies that have joined the campaign in the last few months:

International Network of VENous Thromboembolism

Clinical Research Networks (INVENT-VTE)

 

 

Waitlist Zero

 

 

HIV i-base

 

 

 

ecancer

 

Herpes Viruses Association & Shingles Support Society

 

 

 

Australian Pain Management Association

 

British Dupuytren’s Society

 

 

 

 

Behcet’s UK

 

 

Bad Science Watch

 

 

Brains Trust

 

 

 

Arrhythmia Alliance

 

Join us:

The success of MoreTrials depends upon as many organisations and people interested in trials joining us.

Your organisation might do trials, maybe in a university or industry it doesn’t matter, please join us. You might regulate trials or be involved in research governance. You might fund research or be a patient group.

You might be none of these, but you and/or your group just wants to help us make it much easier to do randomised trials.

Thank you

 

A new MSc by distance learning on how to do randomised trials well

The MSc in Clinical Trials is a two year part-time distance learning course that provides in-depth training in the principles and practice of conducting large-scale, randomised clinical trials. The course has been developed in collaboration with the European Heart Academy, and the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

 

 

Calling all clinical trialists and patient groups: which path will you take?

Everybody agrees that ICH-GCP needs renovation and it has now become clear that two very different pathways are emerging to take this forward.

One of these pathways involves ICH – whose membership is limited to some of the regulators and some pharma companies – spending something like the next 18 months to 2 years behind closed doors to come up with a totally revised version of GCP and then putting a final draft out for public comment. This reality became clearer recently when ICH published the names of the members of the “expert” working group to take this forward:

I only recognise one of the names and there is no accompanying information on what trial expertise these so called “experts” bring to the table. We have repeatedly over the last four years raised the concern that all stakeholders concerned with clinical trials, but particularly academic trialists and patient groups, must be involved in the development of a new GCP (for example, our March 2017 letter setting out these concerns and which, incidentally, we never received a response from ICH).

 

 

So, looking at the membership my questions to ICH are as follows:

  1. What specific clinical trial expertise do the members of the “expert” working group on GCP have? What meaningful trials have they done?
  2. Where are the academic trialists in the membership?
  3. Where are the patient groups in the membership?

I will put these questions to ICH and, if we get a response, I’ll let you know.

Thankfully, there is a second pathway. This is the one recently set up by the Wellcome Trust, the Gates Foundation and African Academy of Sciences which you can learn more about here. This joint initiative sets out to develop new principle-based guidelines for running clinical trials. It is early days yet but the initial signs are really good with a commitment to develop the guidelines in an open and transparent way and the appointment of a leading trialist to lead the initiative.

So, we are in interesting times where we have a choice between the first pathway proposed by ICH where everybody in the trial community effectively buries their heads in the sand for the next 18 months to two years all the time hoping that the so called “experts” come up with something that works, something much, much better. By contrast, the second pathway sets out to develop a new guideline to replace GCP that is based upon the key principles to do a randomised trial well and which involves from the outset everybody in the trial community.

MoreTrials supporter and trialist PJ Devereaux from McMaster summed it up nicely in feedback to ICH on the original creation of ICH-GCP with the following analogy:

“Imagine creating a regulation for putting out fires and forgetting to ask firefighters for their input. Sounds absurd I know, but that’s exactly what we’ve done in regulating trials by not involving trialists”

It looks to me like we are making the same mistake again.

I know which pathway I’m going to take.  If you are a trialist or a patient group it is time for you to decide which pathway you are going to take?

 

A randomised trial of continuous subcutaneous insulin infusion versus multiple daily injections in children and young people newly diagnosed with type 1 diabetes

Type 1 diabetes is a common chronic condition of childhood that requires subcutaneous injection of insulin in doses calculated according to carbohydrate consumption, physical activity and blood glucose measurements. Poor glycaemic control is associated with poor clinical outcomes, including impaired memory, poorer cognitive outcomes, increased risk of depression and poor growth. In the longer term, vascular complications result in blindness, renal failure, premature heart disease, stroke and amputation. Substantial uncertainty exists as to whether newer forms of treatment, particularly continuous subcutaneous insulin infusion (CSII) are clinically superior to multiple daily injections (MDI).

The present study was a pragmatic, multicentre, open-label, parallel group, randomised controlled trial, randomising participants to either CSII or MDI. Study centres were paediatric diabetes clinics experienced in the use of CSII. Eligible participants had a new diagnosis of type 1 diabetes and were aged between 7 months and 15 years. Randomised treatment started within 14 days of diagnosis of type 1 diabetes. All participants completed a structured education programme on type 1 diabetes and its treatment, which included training on CSII and MDI. Study visits were at 3, 6, 9 and 12 months. The primary outcome measure was HbA1c measured at 12 months. There were a number of secondary outcomes, including the percentage of participants in each arm with HbA1c within the national target range and the incidence of severe hypoglycaemia and diabetic ketoacidosis.

Potential participants were identified from 15 centres in the UK. A total of 976 individuals were assessed for eligibility and of these 689 met eligibility and were invited to participate. A total of 293 consented to participate and were randomised resulting in 144 allocated to CSII and 149 allocated to MDI. Baseline characteristics were similar between the two arms. Intention to treat analysis showed no difference in the primary outcome of HbA1c at 12 months between the two arms (adjusted mean [95% CI] mmol/mol; CSII 60.9 [58.5 to 63.3] vs. MDI 58.5 [56.1 to 60.9]; adjusted mean difference 2.4 [-0.4 to 5.3], P=0.09). There were also no significant differences between the groups for all but one of the secondary outcomes (insulin requirements were slightly higher in those treated with CSII, adjusted mean difference 0.1 units/kg/day, 95% confidence interval 0.0 to 0.2, P=0.01).

In conclusion, the authors state that CSII is neither more clinically effective nor more cost effective than MDI.

You can read the full report here.

Randomised trial of mirtazapine in treatment resistant depression

By 2030, depression is predicted to be the leading cause of disability in high-income countries. Antidepressants are often the first line treatment, however, many patients do not respond to treatment with one study finding that half of those treated failed to experience at least a 50% reduction in depressive symptoms after 12-14 weeks of treatment with a single antidepressant.

Clinical guidelines recommend reconsidering treatment options if the patient shows no response after 4-6 weeks of antidepressant use. Further treatment options are varied and include increasing the dose, switching antidepressants, combining two antidepressants, and including another psychotropic drug, such as lithium or an antipsychotic. A new treatment option is the drug mirtazapine, which is a selective noradrenaline α2 adrenoreceptor and serotonin receptors 2 and 3 antagonist. The present trial determined the effects on depression and quality of life of adding mirtazapine to existing antidepressant medication compared to placebo in treatment resistant depression.

Patients were identified from general practices in the UK. Eligible participants were at least 18 years, had used a serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressant for at least six weeks, were adherent to treatment, had a Beck Depression Inventory, second revision (BDI II) score of 14 or more and met the ICD-10 criteria for depression. Patients were excluded who had bipolar disorder, psychosis, major alcohol or substance misuse and a diagnosis of dementia.

Following informed consent, eligible participants were randomised to either one 15mg capsule of mirtazapine daily for two weeks followed by two 15 mg capsules of mirtazapine for up to 50 weeks, or to identical placebo. Participants were followed up at 6, 12, 24, and 52 weeks. The primary outcome was BDI II at 12 weeks. Analysis was by intention-to-treat.

856 patients were identified as eligible for the baseline assessment and of these 105 declined to take part. A total of 751 attended the baseline interview, but a large number (271) were determined to be ineligible (mostly due to not meeting the depression severity criteria). A total of 480 were randomised comprising 241 randomised to mirtazapine and 239 to placebo.

The two groups had similar baseline characteristics, but some evidence showed that participants in the mirtazapine group had more severe depression. For the primary outcome the mean BDI II score at 12 weeks in those randomised to mirtazapine was 18.0 (SD 12.3) compared to 19.7 (12.4) in those allocated to placebo. After adjustment for the baseline BDI II score and stratification and minimisation variables the confidence interval included the null (adjusted difference in means -1.83, 95% confidence interval -3.92 to 0.27, P=0.09).

For the secondary outcomes the adjusted difference in BDI II score between the groups at 24 and 52 weeks was smaller and included the null (24 weeks: adjusted difference in means −0.85 (−3.12 to 1.43); 52 weeks: adjusted difference in means 0.17 (−2.13 to 2.46). For the other secondary outcomes, the adjusted difference in scores between the groups was small and with only two exceptions included the null. Patients in the mirtazapine were more likely to report adverse events and stop taking treatment.

In conclusion, the authors state that the trial did not find convincing evidence of a clinically important benefit of mirtazapine over placebo when given in addition to an SSRI or SNRI antidepressant for patients who remained depressed after at least six weeks of antidepressant treatment.

You can read the full report here.