Our second clinical trial, SONIA 2, is a four-year long trial. If you choose to take part in SONIA 2, you will need to visit a test centre six times over four years. At your first visit, you will be randomly allocated to one of two groups. One group will receive nitisinone and the other group will receive no treatment. This means there is a 50% chance that you will receive nitisinone.
The existence of a non-treatment group has raised more questions and concerns from patients and their doctors than any other aspect of our clinical trials. There are a number of reasons for having a non-treatment group:
The ‘gold standard’ of clinical trials
The best way to prove nitisinone works in AKU is by comparing a group on nitisinone with a group that is not on nitisinone. The group which doesn’t receive nitisinone is also known as the control group. We need to compare two groups to prove nitisinone slows or stops the progression of AKU.
By comparing the tests and assessments from both groups over the four years, we hope to demonstrate significant differences in the results of the two groups. For example, blood and urine tests may show changes in levels of homogentisic acid (the cause of AKU damage) or bone scans may show different amounts of deterioration.
This approach is known as a randomised control trial or an RCT. RCTs are considered the ‘gold standard’ of clinical trials, as they provide the strongest evidence for the effectiveness of a treatment. Regulatory authorities such as the European Medicines Agency (EMA) and the American Food and Drug Administration (FDA) require a comparison with a control group to approve a new treatment.
We already know a lot about the safety of nitisinone from its use in treating hereditary tyrosinemia type 1 (HT-1). As the doses used in AKU are very low compared to those in HT-1, nitisinone is generally considered safe for use in AKU and is prescribed off-label (see below) in many countries.
However, there is a chance that AKU patients may react differently from HT-1 patients. Comparing the nitisinone and control groups will also allow us to increase our understanding of how AKU patients interact with nitisinone.
Why is there no placebo in SONIA 2?
The control group in an RCT is usually given an existing alternative treatment or a placebo. A placebo is an inactive drug with no effect. As nitisinone can change the urine colour of patients with AKU, you would know very quickly if you were in the placebo group.
For this reason, we decided not to use a placebo in the DevelopAKUre clinical trials. If you take part in SONIA 2, you will be told which group you are in at your first visit.
Is there any benefit to being in the non-treatment group?
In one word – yes. If you are randomised to the non-treatment group, you will receive all of the same assessments as the group receiving nitisinone. You will still have regular contact with AKU experts and a range of other healthcare professionals who will monitor both your AKU and your general health.
If the clinical trials are successful, the comparison between the 2 groups will allow us to apply for the approval of nitisinone for use in AKU. This will improve local access to nitisinone for AKU patients.
Why does the trial have to last four years?
A four-year long trial will strengthen the evidence that nitisinone is effective over a long period of time. Previous trials were too short to show any effect of nitisinone on AKU symptoms as these symptoms can take a long time to develop.
If nitisinone is already available off-label, why bother with a clinical trial?
As nitisinone is already approved for use in HT-1, some doctors also prescribe it for use in AKU. This is known as off-label use. However, policies on off-label use vary greatly between countries and even regions. There is also no guarantee AKU patients will continue to receive nitisinone off-label if nitisinone is not approved for use in AKU.
Many countries in Europe are tightening their health budgets, and off-label use may be reduced as a result. As mentioned above, our understanding of how nitisinone and AKU interact is still limited. Patients on the clinical trial will be monitored much more closely than most patients taking nitisinone off-label.
This will allow any problems to be identified and dealt with early on.
If you have any questions about this blog post or about the DevelopAKUre clinical trials, please contact me by email at email@example.com. You can also register your interest at the bottom of the page and I will get back to you.
DevelopAKUre is a series of major international clinical trials, run by a consortium of 12 European partners. It aims to study a potential new drug, called nitisinone, and assess its potential effectiveness in treating the rare disease, alkaptonuria (AKU).
DevelopAKUre is co-funded by a grant from the European Commission. This website is run by a UK patient group, the AKU Society. Learn more about AKU on the AKU Society's What is AKU page.
In today’s blog Chief investigator Prof. Ranganath reinforces the need for SONIA 2 pat.. ...more