17th December 2020

The SIDEROS study was a clinical trial for patients with Duchenne muscular dystrophy that was stopped earlier this year.

The trial aimed to analyse the effectiveness of idebenone compared to placebo in delaying the loss of respiratory function for DMD patients receiving glucocorticoid steroids.

An interim analysis, however, revealed the clinical trial was unlikely to meet its objectives.

The following summary has been produced by patient groups working in partnership with the manufacturer Santhera to explain more about the trial, what its goal outcomes were, and why it was stopped.

You can read it below or download here.

Summary: 

• The SIDEROS study was a clinical trial of 256 participants with Duchenne muscular dystrophy (DMD). 

• It aimed to analyse the effectiveness of idebenone compared to placebo in delaying the loss of respiratory function in DMD patients who were receiving glucocorticoid steroids. 

• Santhera requested that the Data and Safety Monitoring Board (DSMB) conduct an interim analysis of the results so far. The DSMB is a committee that is independent of the company and people carrying out a clinical trial. It is made up of clinical research experts, such as physicians and statisticians, and patient advocates who monitor the progress of a clinical trial and review safety and effectiveness data while the trial is ongoing. 

• The interim analysis showed that that the clinical trial was unlikely to achieve its objectives. This means that the key outcomes (also called primary endpoint results) – measured at the end of a clinical trial to see if a given treatment worked – were not likely to be of clinical relevance and it would be unethical to continue the study. 

• Based on the DSMB’s recommendations that it would be unethical to continue, Santhera has stopped the SIDEROS study. 

Information about the SIDEROS Study 

What is the SIDEROS study? 

• SIDEROS was a study evaluating the effectiveness of the drug idebenone in delaying the loss of respiratory function in patients with Duchenne muscular dystrophy (DMD) who are taking glucocorticoid steroids. 

• An efficacy trial determines whether an intervention - in this case idebenone - works as expected under ideal circumstances. 

• The study was a double-blind placebo-controlled Phase 3 trial. This means that neither researchers nor patients knew if they were receiving the drug or the placebo (an inactive form of the drug). Patients on any stable glucocorticoid treatment scheme and, regardless of the underlying dystrophin mutation or ambulatory status, were randomly assigned to one of two groups. 

• The trial would give one group oral idebenone (900 mg/day, in three divided doses) and the other would receive placebo for 18 months. 

Which patients were included in the SIDEROS study? 

• Participants were aged 10 or older and had a forced vital capacity percent predicted (FVC%p) of less than 80%. They were also in respiratory function decline at the start of the study. 

• Forced vital capacity (FVC) is the total volume of air that can be forcibly exhaled from the lungs after taking a deep breath in. 

• High FVC scores are a sign that the lungs are inflating to full capacity. 

• In DMD, weakness of the breathing muscles causes a gradual decline in FVC. This indicates that the total volume of air within your lungs reduces over time, eventually requiring the need for non-invasive breathing support. 

What were the primary objectives of the study? 

• To assess the effectiveness of idebenone compared to placebo in delaying the loss of respiratory function in patients with DMD who were receiving glucocorticoid steroids. 

• This was measured by using clinic-based spirometry to track changes in people’s Forced Vital Capacity percent predicted (FVC %p) from the start of the study to week 78. 

How many patients were enrolled into the study? 

• 256 participants were been randomised into the SIDEROS study. 

In how many countries and centres is the SIDEROS study being run? 

• The SIDEROS study is an international multi-centre study run in 14 countries and approximately 60 clinical trial sites across Europe, North America and Israel. 

• There are seven study centres in the U.K. 

What’s the difference between the SIDEROS and DELOS study? 

• The DELOS study (which was completed in 2014) assessed the effectiveness of idebenone in delaying the loss of respiratory function for DMD patients who had either never taken or had stopped taking glucocorticoid steroids a year prior to the start of the study. 

• In SIDEROS, the efficacy of idebenone was being assessed in patients who were taking glucocorticoid steroids in addition to idebenone. 

How has COVID-19 impacted the study? 

• The global COVID-19 pandemic did not adversely impact the SIDEROS study. 

• Santhera made provisions allowing for remote safety monitoring, study medication delivered direct to patients and additional time between scheduled study visits. 

SIDEROS STUDY INTERIM ANALYSIS 

What is an interim analysis in a clinical trial? 

• An interim analysis is an analysis of the trial data that is conducted before the trial has been completed. 

What were the possible outcomes of the interim analysis? 

• Typical outcomes of interim analyses are to either stop the clinical trial because the trial treatment is showing more effectiveness than expected (called compelling efficacy), to continue the clinical trial as originally planned, or to stop the trial because it is unlikely to achieve its objectives (called futility). 

Was the interim analysis planned? 

• The decision to do the interim analysis was taken part way through the trial.In order to do this Santhera had to request a change to the document that describes exactly how the clinical trial takes place – called the clinical trial protocol. 

Why did Santhera conduct an interim analysis? 

• Santhera wanted to determine if the SIDEROS study could stop earlier than originally planned or should continue. 

• This analysis was undertaken to ensure study participants were not exposed to a placebo in the trial for longer than necessary and to possibly accelerate access to a potential new therapy for patients. 

Did Santhera conduct the interim analysis because of Committee for Medicinal Products for Human Use (CHMP) issues? 

• No, the decision to conduct an interim analysis was taken after analysis showed that the current sample size of the study indicated that the SIDEROS study has a very high power (>99% power) for the primary endpoint results. 

This analysis was undertaken to ensure study participants were not exposed to a placebo in the trial for longer than necessary and to possibly accelerate access to a potential new therapy for patients. 

How many patients were included in the interim analysis? 

• In agreement with regulatory authorities, data from 197 of the 256 patients randomized in the study were used for the interim analysis. 

How was the interim analysis conducted? 

• The independent Data and Safety Monitoring Board (DSMB) was asked to perform the interim analysis. 

• The DSMB estimated the treatment effect on the difference between those treated with the drug and those with the placebo using measurements of forced vital capacity percent predicted, (FVC%p). 

• The DSMB then made a recommendation to Santhera based on pre-defined criteria. 

• Only the DSMB had access to the unblinded data – meaning they knew who had received idebenone and who had been given the placebo – until they issued the recommendation. 

• Once Santhera had accepted the recommendation, they were provided with high-level data supporting the recommendation. 

Did Santhera unblind the data during the interim analysis? 

• Only the DSMB had access to the unblinded data. All other parties, including Santhera, remained strictly blinded to any study related information. 

What does futility mean and how was this determined? 

• Futility in this study meant the chance of the trial being able to show idebenone was effective in the planned final analysis had become so small that continuation of the study could not be justified any more. 

Does futility mean the study failed and were patients possibly harmed by taking part in the study? 

• All clinical trials try to determine the benefits and risks of a therapy. 

• Conducting the interim analysis and stopping the study for futility ensures that participants are not exposed to a treatment that is unlikely to be of clinical benefit or exposed to placebo for longer than is necessary. 

• The futility criteria were based on efficacy data only. The DSMB has been reviewing the safety data throughout the conduct of the study and has not detected any new safety concerns. 

What is the clinical relevance of this outcome? 

• The DSMB’s decision to recommend stopping the clinical trial was based on the analysis that showed it was unlikely there would be a difference in outcomes between the idebenone and placebo groups at the end of the clinical trial. 

• This means the results of the primary endpoint – the main result that is measured at the end of a clinical trial to see if a given treatment worked - are not likely to be of clinical relevance and it would be unethical to continue the study. 

What does this mean for the SIDEROS study? 

• Based on the DSMB’s recommendations, Santhera has stopped the SIDEROS study. 

Did COVID-19 impact the interim analysis? 

• The global COVID-19 pandemic did not adversely impact the SIDEROS study or the conduct of the interim analysis. 

Impact on SIDEROS study participants and participants of the SIDEROS extension study 

What will happen to participants in the SIDEROS study? 

• All study participants will be asked to stop treatment immediately and attend an End of Study visit for safety assessments, approximately four weeks after treatment is stopped. 

• If you are worried as a trial participant or guardian, you should contact your clinical trials team for further guidance. 

What happens to study participants who have completed the SIDEROS study? 

• Participants who have completed the SIDEROS study or have rolled into the SIDEROS-Extension study, will be informed about the study discontinuation through their clinical trial site. 

• They will receive guidance on how to terminate treatment immediately. 

Will Santhera continue to support the current extension studies? 

• No, based on the DSMB’s recommendation to stop the SIDEROS study, Santhera will also stop the SIDEROS-Extension study. 

What will happen to study participants in the SIDEROS- Extension study? 

• All patients in SIDEROS-Extension will be asked to stop treatment immediately and attend the end of study visit for safety assessment, approximately four weeks after treatment is stopped. 

• If you are worried as trial participant or guardian, you should contact your clinical trial team for further guidance. 

When will study participants know whether they were on placebo or active treatment? 

• Santhera will organize the provision of this information to study participants through their clinical trial site as part of the study close out activities. 

Will Santhera be providing psychological support to those patients who have been in SIDEROS? 

• Study participants who feel they require psychological support should speak to their clinical study site. 

What will happen to the data from SIDEROS now? 

• Santhera is currently analysing the interim dataset. A paper summarising the data will be submitted to a scientific journal. 

PULDYSA (IDEBENONE) REGULATORY STATUS 

Did Santhera conduct the interim analysis to support the current EU submission? 

• No, the decision to conduct an interim analysis was taken after conducting a protocol-defined re-estimation of the sample size. This had indicated the SIDEROS study had a very high power (>99% power) for the planned final analysis. 

How will the interim analysis data be used for regulatory purposes? 

• Santhera will withdraw the ongoing marketing authorization application for Puldysa in the EU. SIDEROS results will not be submitted for an initial US New Drug Application (NDA) in DMD. 

What does this mean for regulatory approval in the EU? 

• Santhera will withdraw the ongoing marketing authorization application for Puldysa in the EU. 

What does this mean for regulatory approval in the US? 

• SIDEROS results will not be submitted for an initial US NDA in DMD. 

EARLY ACCESS / PATIENT ACCESS 

What will happen to the Early Access to Medicines Scheme (EAMS) in the UK? 

• Santhera has spoken to the Medicines and Healthcare products Regulatory Agency (MHRA) and additional guidance has been provided to physicians to inform families participating in EAMS. 

• If you are taking idebenone in the EAMS scheme your physician will contact you. 

Does the company have plans for any additional early access studies in other countries? 

• Santhera has made the difficult decision to withdraw its marketing authorisation application and discontinue its development program for idebenone in DMD. 

• This means no further Early Access Schemes can be made available to DMD patients for idebenone. 

COMMERCIALISATION PLANS 

Will the company still try to gain approval in EU for Glucocorticoid non-users? 

• Santhera has made the difficult decision to terminate the Puldysa (idebenone) clinical development program in DMD. 

Will Puldysa be launched in the US? 

• Santhera has made the difficult decision to terminate the Puldysa (idebenone) clinical development program in DMD. 

Why has Santhera withdrawn the conditional marketing authorisation approval for Glucocorticoid nonusers? 

• The interim analysis was driven by a protocol-defined re-estimation of the sample size and not by a CHMP requirement. 

• However a positive outcome of the SIDEROS interim analysis could have served as additional evidence to the DELOS trial. 

• The DSMB’s recommendation to stop the SIDEROS trial for futility does means there is no supportive data for the DELOS trial. 

Santhera has therefore taken the decision to withdraw the application. 

What will happen to the vamorolone program? 

• Santhera remains fully committed to continuing the vamorolone program in DMD. 

What does this mean for Santhera and its commitment to DMD? 

• Santhera is committed to continuing developing novel therapies for rare neuromuscular diseases including DMD, (in addition to vamorolone) to address unmet needs. 

REFERENCES 

1. Buyse et al. 2015; Lancet 385 :1748-57 

2. McDonald et al. 2016; Neuromuscl Disord. 26(8):473-480 

3. Servais L, et al. Neuromuscl Disord. 2020. pii: S0960-8966(19)31164-2