What is ataluren?
Ataluren (formerly referred to as PTC124®) is being studied as a potential treatment for cystic fibrosis caused by a specific genetic mutation, or change in the genetic code. Developed by PTC Therapeutics (PTC), ataluren targets the genetic mutation known as a nonsense mutation. Nonsense mutations, also known as premature stop codons, are errors in the genetic code that cause a disorder by prematurely stopping the production of a critical protein. In the case of cystic fibrosis (CF), this essential protein is the cystic fibrosis transmembrane conductance regulator (CFTR). Approximately 10 percent of cases of CF are caused by a nonsense mutation1 although rates may vary depending upon ethnicity and country of origin.
For patients with nonsense mutation CF (nmCF), ataluren has the potential to treat the underlying cause of the disease by allowing the cellular machinery to overcome the nonsense mutation and produce a functioning CFTR protein.
Ataluren has the potential to treat a number of genetic disorders caused by a nonsense mutation. The Committee on Human Medicinal Products, a part of the European Medicines Agency, has adopted a positive opinion regarding PTC's application for a conditional marketing authorization of ataluren under the brand name Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy.
1Based on Cystic Fibrosis Foundation Registry data.
If a patient has only one nonsense mutation will ataluren still have the potential to work?
Ataluren has the potential to work even if only one nonsense mutation is present. Everyone has two copies of the CFTR gene, one inherited from each parent. People with CF have a mutation in both copies because a single inherited mutation will not cause CF. Often the two mutations are different, such as Delta 508F (the most common CF mutation) and G542X (a common CF nonsense mutation).
What is the purpose of ACT CF?
The main goals of the trial are to find out whether ataluren can:
- positively affect lung function in patients with CF
- reduce the number of pulmonary exacerbations
- help improve overall patient quality of life
- be given safely to adults and children for a long period.
The study will also evaluate whether ataluren can improve general well-being and the number of hospitalizations. The study is intended to generate the information required to support approval of ataluren by regulatory authorities in Europe and the United States.
How does ACT CF differ from PTC's previous Phase 3 study in cystic fibrosis?
Results of the previous Phase 3 study in nmCF showed a trend in favor of an ataluren treatment effect in FEV1 (the amount of air that can be expelled from the lungs in one second) and in the rate of exacerbations (periods when lung disease worsens) versus placebo. The effect was most marked in patients who were not receiving chronic inhaled aminoglycoside antibiotics such as Tobi® (Tobramycin Nebuliser Solution). This group represented approximately one half of those in the study. In order to confirm this larger treatment effect, only patients who do not use inhaled aminoglycoside antibiotics chronically will be enrolled in the new study. Other changes in the design of the new study are intended to make participation easier for patients.
What is the design of ACT CF?
The study will enroll approximately 208 patients with nmCF at research centers in North and South America, Canada, Europe, Australia, and Israel. ACT CF is randomized, double-blinded and placebo-controlled — participants will be randomly assigned to receive either ataluren or placebo (a substance that looks and tastes the same as ataluren, but does not actually contain the drug) for 48 weeks. Each participant will have an equal chance of being assigned to either group. The patient, patient's family, the study investigators, site staff, and PTC Therapeutics personnel cannot choose the group and, barring exceptional circumstances, will not know which treatment each participant is receiving until after the study is over.
Why won't all participants in ACT CF receive ataluren?
In order to determine whether ataluren improves symptoms of CF compared to current standard of care, it is necessary to contrast the results in participants receiving ataluren with those in participants who are receiving placebo. However, each participant who successfully completes the trial will be eligible to enter into an extension study that will last at least another 48 weeks in which every participant will receive ataluren.
Who is eligible to participate in ACT CF?
More complete inclusion and exclusion criteria are available at www.clinicaltrials.gov and will be explained in detail by the doctors conducting the study, but key considerations follow. Potential participants must:
Have a nonsense mutation, which is determined through a DNA blood test to evaluate the CFTR gene (genotyping). Parents or caregivers of patients who have not had this test should consider discussing it with their doctor or genetic counselor.
- Be at least 6 years old and weigh and least 16 kg (about 35 pounds).
- Have adequate lung function and be able to do a breathing test resulting in values between 40% and 90% of those predicted for healthy people of similar age, sex, and height.
- Not have used inhaled antibiotics of the aminoglycoside class for at least 4 months. The most commonly used antibiotic of this type is tobramycin (TOBI®).
- Have no serious abnormalities of the liver, kidney, or adrenal functions, or life-threatening complications of CF or other diseases.
The decision as to whether a patient is appropriate for the study is ultimately made by the principal investigator at the study site who, in communication with the patient and with the family, is best able to consider the possible risks and benefits for each potential participant.
Why won't children under age six be able to participate in ACT CF?
Children participating in the study will need to be able to reliably perform the required tests. The primary measure of the potential effectiveness of ataluren in this trial will be change in lung function, as measured by breathing tests (spirometry). Because it is often difficult for very young patients to perform spirometry the results may not be reliable in children under six years of age, and consequently the trial is limited to older participants.
Will the use of other CF treatments prevent patients from qualifying for participation in the trial?
Patients who are receiving other approved treatments for CF, or CF-related conditions, can participate in the trial provided they meet all eligibility criteria (see www.clinicaltrials.gov). However, it is important that participants who are taking other medication are on a stable dose and medication schedule, and are willing to remain on the same dose and schedule throughout the study, unless there is a medical need to change, or add to, the treatment.
Details of the types of medication that are permitted during the trial will be provided by the study doctors.
Patients cannot participate if they are simultaneously participating in any other therapeutic clinical trial.
What will participation in the trial involve?
Before being considered for enrollment in the trial and undergoing testing, or receiving study medication, a patient (and a parent or guardian, if the patient is a minor) must be informed about the trial by the medical researchers. This requires signing a document called an Informed Consent, indicating a willingness to participate. The Informed Consent explains the trial in great detail to allow families to assess the risks and benefits of participation. Children may also be asked to sign a less detailed assent form that explains the basics of the trial in age-appropriate language. A copy of each signed form is provided to the patient and family.
After the consent process, the patient will be screened to determine whether he or she is eligible to participate in the study. These screening procedures will usually be done at a clinic visit during the four-week period before treatment would be scheduled to start. Screening will determine whether a potential participant in the trial meets the study entry requirements, and can contribute data that will help achieve the study goals.
In this study, participants who receive ataluren will be compared to those who do not. The participants will be divided into 2 groups of about 104 patients each. The amount of drug or placebo used is determined by body weight in kilograms (1 kilogram equals 2.2 pounds):
- Group 1 will receive ataluren at a dose of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening
- Group 2 will receive a placebo (inactive powder that looks and tastes the same as ataluren) at a dose of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening.
- The drug or placebo is supplied in a packet as a powder that has a mild vanilla flavor. It can be mixed with water, milk, or certain semi-solid foods.
During the 48 weeks of the clinical trial, participants will visit the research center at least every eight weeks. During these visits, participants will perform spirometry (breathing tests), have blood drawn, have other tests and evaluations and be asked about their CF-related symptoms and quality of life.
Following the study, each patient or parent will be asked to provide information on the patient's general health at six- to 12-month intervals over a five-year period. This survey may be completed at the research center during a routine visit or by telephone.
If a participant withdraws from the study early or does not wish to enter the extension study (see next question), a short-term follow-up visit will be performed 4 weeks after stopping the drug or placebo to document the general health of the participant.
Will study participants who receive placebo during the trial be eligible to receive ataluren?
At the end of 48 weeks it is planned that in countries where ataluren is not commercially available for the treatment of CF all participants who complete the trial will have the opportunity to enter into an extension study in which they will receive ataluren.
Where is ACT CF being conducted and how long will it be accepting patients?
Study sites are planned in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, France, Germany, Israel, Italy, Netherlands, Poland, Spain, United Kingdom and the United States. All sites will be posted on www.clinicaltrials.gov under the identifier NCT02139306 and on http://www.ptcbio.com/ataluren_trial_sites. The study will continue enrolling new patients until the necessary number of participants has been reached. The large number of trial sites makes it difficult to know when that will occur, so patients are encouraged to enroll as soon as they are able. The faster the study can be completed, the sooner the results can be known.
How can a patient enroll in ACT CF?
All of the currently planned sites for ACT CF will be posted on www.clinicaltrials.gov under NCT02139306 and on http://www.ptcbio.com/ataluren_trial_sites. As soon as each site is open to enroll patients the necessary contact details will be provided on these websites so that patients or their families will be able to contact the site of their choice to enquire directly about participation. In countries where there are no trial sites patients who meet the eligibility criteria for the trial may be able to enroll at a site in another country. Please contact firstname.lastname@example.org for additional information.
Is there any cost to participate in the trial?
All costs of physical examinations, screening, laboratory and other tests, as well as the cost of the drug, are covered by PTC Therapeutics. Reimbursement will be made for reasonable costs of travel, meals, and lodging necessary for clinic visits, subject to limitations that will be explained at the trial site.