Moving treatment forward for hereditary angioedema
If you have patients living with hereditary angioedema (HAE), you may know the impact it has on their everyday lives. But research on managing HAE is advancing, and now, you can help lead the way.
What is STOP-HAE?
The siRNA Targeting of Prekallikrein (PKK) for Hereditary Angioedema (STOP-HAE) clinical trial is a Phase 3, randomized, double-blind, placebo-controlled study that is evaluating the investigational drug ADX-324 in adults with HAE Type I and Type II. It aims to discover whether ADX-324 may help improve how we manage HAE by preventing attacks before they happen and reducing their severity if they do.
What makes ADX-324 different?
ADX-324 is a siRNA investigational drug designed to silence KLKB1 messenger RNA (mRNA), which regulates the production of PKK. PKK is a key protein that triggers the bradykinin cascade, leading to swelling attacks in people with HAE. By lowering the concentration of PKK through this RNA interference (RNAi) mechanism, ADX-324 aims to interrupt the production of the mRNA that creates the PKK protein and therefore, helps prevent HAE attacks.
Although there are already long-term treatments approved to prevent HAE attacks, ADX-324 may decrease the amount of PKK to a greater degree, which may allow for less frequent dosing regimens and longer durations of sustained, attack-free periods compared to currently available HAE therapies.
It also means that ADX-324 has the potential to ease the daily or weekly burden of current treatment and improve your patient’s quality of life.
What is the study design?
STOP-HAE is a Phase 3 study that will evaluate the efficacy of two dose levels and regimens of ADX-324 in preventing HAE attacks compared to a placebo.
All participants must complete a minimum 4 week observation period regardless of whether they are on a long-term prophylactic therapy (LTP) or not to confirm eligibility and establish a baseline for attacks. The length of the washout period is dependent on LTP medication with potential extension, if needed. Other than the specified LTP therapies, participants may maintain all other medications.
Participants who meet the screening eligibility criteria will be randomized to 1 of 3 study groups (ADX-324 240mg, ADX-324 300mg or placebo) in a 1:1:1 ratio.
Optional extension study
There is a planned long-term extension study, ADX-324-302 or STOP-HAE Extension Study, for those who complete all required protocols in the primary study. In this extension study, all participants, including those on the placebo, will receive the investigational drug, ADX-324, for up to an additional 3 years. Participants who received ADX-324 during the core study will continue the same dose, whereas those who received the placebo will receive ADX-324 at either 240mg or 300mg. Should a participant end participation early in the primary study, they will not be eligible to participate in the extension study.
Who can take part in the study?
To be eligible for the study, your patients must:
- Be 18 years old or older at the time of screening
- Be officially diagnosed with HAE Type I or Type II
- Be willing to comply with all study requirements for the duration of the study
- Have no significant medical history that could interfere with the study (such as uncontrolled hypertension, diabetes, cardiovascular disease, bleeding diathesis, renal or hepatic diseases)
- Have access to, and the ability to use, at least one acute HAE therapy to treat attacks (e.g. plasma-derived or recombinant C1-INH concentrate or BK2-receptor antagonist) that has previously been shown to be effective.
- Have experienced >1 investigator-confirmed HAE attack in the first 4 weeks of screening, or >2 investigator-confirmed attacks in 8 weeks.
- Be able to provide written informed consent and be willing to comply with all study requirements for the duration of the study (such as completing a daily eDiary)
- Have a mobile phone to register and set up their eDiary account (once registered, they may complete their daily eDiary updates using their computer or tablet). If a participant cannot update the eDiary regularly, it may affect their ability to remain in the trial.
What your patients can expect
Screening – 4 to 8 weeks
Before we start any tests or procedures, patients will be asked to read and sign a consent form. The study team will then check their eligibility through medical history, questionnaires, and health assessments.
If your patient is taking a preventative medication, they’ll need to washout before the screening period. The duration of washout will be dependent on the preventative medication. Trial doctors will guide patients through this process and patients will be able to take their on-demand, or rescue, medications should he/she have a HAE attack.
This screening period will also include completing QoL (qualify of life) questionnaires, using a daily eDiary within the application to report HAE attacks should these occur and basic medical tests, such as:
- Measurement of vital signs (blood pressure, breathing rate, heart rate, and temperature)
- Electrocardiogram (ECG) heart test
- Blood and urine sample collection
- Questions about their quality of life, current HAE symptoms, any medications they have taken recently or are currently taking and medical history
Participants will also learn how to use the study app and eDiary which will be used to track HAE attacks throughout the duration of the primary and extension studies. Trial doctors and study team will teach participants how to use the eDiary at the screening visit.
Study and follow-ups – 25 weeks
Patients will be randomly assigned to receive ADX-324 240mg, ADX-324 300mg or the placebo (saline solution) in a 1:1:1 ratio. Both the investigational drug and placebo will be given as a subcutaneous injection.
Regardless which group they’re in, your patients will have regular visits for health checks, blood and urine tests, ECGs, and support from our study team. They’ll also be required to track their symptoms using the eDiary within the patient app.
These assessments may include:
- Physical examination
- Measurement of vital signs (blood pressure, breathing rate, heart rate, and temperature)
- Blood and urine sample collection
- Additional blood tests to see how their body is reacting to the study drug
- ECG heart test
- HAE attack assessment to check the frequency and severity of their attacks should they be experiencing HAE attacks
- Questionnaires about symptoms they may or may not be experiencing, quality of life and medications they are taking.
While in the study and follow-up period, participants who choose to take part may be able to also opt-in to having home nursing visits for certain visits. On-demand, rescue medications taken for HAE attacks by participants during the study (including the screening period) may be reimbursed (if allowed by regulatory authorities) while enrolled in the primary study or the extension study.
There will be an optional extension study, after the initial trial completion, where all participants will receive ADX-324 at the same dose, if initially assigned to a treatment group. If in the primary study, if a participant were assigned the placebo, in the extension study, the participant would be assigned to receive treatment.
Optional extension study – up to 3 years
If eligible, patients who complete the primary study, ADX-324-301 or STOP-HAE, may be invited to take part in a follow-up extension study, ADX-324-302, involving the same investigational drug for up to an additional 3 years. This study, named STOP-HAE Extension Study, will only be available to those participants who complete the primary study.
All participants in the extension will receive ADX-324, including those initially on the placebo. Patients already on the investigational drug will continue at their current dose, whereas those who are not will start either ADX-324 240mg or ADX-324 300mg depending on whether they received 1.2ml or 1.5ml of the placebo, respectively. All participants will receive ADX-324 at no cost.
FAQs
Are there any costs to take part in the study?
No, participants will receive all study-related procedures and the investigational drug at no cost. Participants will be responsible for their normal healthcare costs. Patient out-of-pocket expenses related to participation in the study, such as out-of-pocket costs for rescue medications, travel expenses and accommodations, may be covered per country and local regulations.
How long will the study last?
The initial study will last around 7-8 months, and up to 3 years if participants are eligible and choose to participate in the extension.
What is the washout period for participants on other preventative medications?
The duration of the washout period is medication dependent. Guidelines for exposure and use of the following long-term prophylactic therapies (LTPs) are as follows:
- C1-INH (CINRYZE, HAEGARDA, RUCONEST): 2 weeks prior to screening
- Berotralstat (ORLADEYO): 3 weeks prior to screening
- Lanadelumab (TAKHZYRO): 8 weeks prior to screening
- Androgen use: 12 weeks prior to screening
How are patients randomized for the initial study period?
Randomization into the STOP-HAE study will be stratified by baseline HAE attack rate (1 to <2 attacks per 4 weeks, 2 to <3 attacks per 4 weeks, or ≥3 per 4 weeks).
How are patients evaluated and qualify for the study?
The screening period for STOP-HAE can take up to 8 weeks.
Participants with ≥1 investigator-confirmed HAE within 4 weeks of signing consent will be eligible for randomization. Those without ≥1 may be observed for up to an additional 4 weeks, and need ≥2 investigator-confirmed attacks in the total period to proceed to randomization.
Participants who experience ≥3 investigator-confirmed attacks can proceed directly to randomization if all other eligibility criteria are met.
How will the study drug be administered?
ADX-324 will be administered as a subcutaneous injection once every 3-6 months depending on the dose the participant is randomized to in the primary study.