Celiprolol for Ehlers-Danlos Syndrome

(DiSCOVER Trial)

Overseen By Jonathan Cotliar, MD; Ph.D.

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Acer Therapeutics Inc.

Must not be taking: β-blockers

Disqualifiers: Pregnancy, Arterial rupture, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 40 months

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether celiprolol, a medication, can benefit individuals with a specific type of Ehlers-Danlos syndrome (vEDS) caused by a COL3A1 gene mutation. The study compares celiprolol's effects to a placebo (a pill with no active medicine) to determine if it can prevent complications like blood vessel problems. Individuals with a confirmed COL3A1-positive genetic test who can stop using certain heart medications might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

You will need to stop taking β-blockers (a type of heart medication) before joining the trial. The protocol does not specify about other medications.

Is there any evidence suggesting that celiprolol is likely to be safe for humans?

Research shows that celiprolol is generally well-tolerated by people with vascular Ehlers-Danlos syndrome (vEDS). Studies have found that celiprolol can help reduce serious blood vessel problems, which are common in people with vEDS. While these studies mainly focus on the treatment's effectiveness, they also provide some information about its safety.

Other research indicates that celiprolol is already used in Europe to treat vEDS, suggesting it has passed safety checks there. However, a long-term study found that even with celiprolol, people with vEDS may still experience blood vessel issues. This means that while celiprolol can be helpful, it doesn't eliminate all risks associated with vEDS.

In summary, celiprolol appears to be a safe option for many people with vEDS, but like any treatment, it might not work the same for everyone. Prospective trial participants should discuss any concerns with a healthcare professional. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Ehlers-Danlos Syndrome?

Most treatments for Ehlers-Danlos Syndrome (EDS), particularly the vascular type, focus on symptom management and supportive care, like physical therapy or pain management. Celiprolol stands out because it specifically targets the cardiovascular complications of EDS. It works as a selective beta-blocker that helps strengthen blood vessel walls, potentially reducing the risk of life-threatening complications like arterial dissections or ruptures. Researchers are excited about celiprolol because it offers a targeted approach to managing EDS, which could significantly improve patients' quality of life by addressing the root cause of some of the most serious symptoms.

What evidence suggests that celiprolol might be an effective treatment for Ehlers-Danlos Syndrome?

Research has shown that celiprolol, which participants in this trial may receive, can lower the risk of serious blood vessel problems in people with vascular Ehlers-Danlos syndrome (vEDS). One study found that celiprolol effectively prevented major issues like blood vessel ruptures or tears compared to those who didn't receive any treatment. After almost four years, patients taking celiprolol experienced fewer serious complications. Another study found that adding irbesartan to celiprolol further reduced the risk of artery-related problems. These findings suggest that celiprolol could be a promising option for managing vEDS. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for individuals with genetically confirmed vascular Ehlers-Danlos Syndrome (vEDS) who are at least 15 years old. Participants must not have had certain medical events like arterial rupture in the past 6 months, be pregnant, or use β-blockers within 28 days prior to starting the study.

Inclusion Criteria

I can stop taking β-blockers 28 days before joining the study.

I have a confirmed genetic mutation in the COL3A1 gene.

I am 15 years old or older.

Exclusion Criteria

Any medical condition that in the opinion of the Investigator may pose a safety risk to the patient in this study, which may confound efficacy or safety assessment, or may interfere with study participation

I am not taking any medications that are not allowed in the study.

I have not had any major artery, uterus, or intestine ruptures in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either celiprolol or placebo in a double-blind manner, with titration over the first 4 months

40 months

Decentralized visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term with celiprolol

What Are the Treatments Tested in This Trial?

Interventions

• Celiprolol

Trial Overview

The study tests Celiprolol's effectiveness against a placebo in patients with vEDS. It's a Phase 3 trial where participants are randomly assigned to receive either Celiprolol or a placebo twice daily, and it uses remote monitoring methods.

How Is the Trial Designed?

Group I: Placebo BID Experimental Treatment 1 Intervention

Placebo twice daily (BID) Placebo given orally to mimic ACER-002 (celiprolol) administration

Group II: ACER-002 (celiprolol) 200 mg BID Experimental Treatment 1 Intervention

ACER-002 200 mg twice daily (BID) (after titration): 200 mg morning and 200 mg evening: 400 mg total daily dose Titration: Day 1 to Month 1 - 100 mg once daily (QD) evening: 100 mg total daily dose Month 2 to Month 3 - 100 mg morning and 100 mg evening: 200 mg total daily dose Month 3 to Month 4 - 100 mg morning and 200 mg evening: 300 mg total daily dose Month 4 to End of Treatment Period (BID) - 200 mg morning and 200 mg evening: 400 mg total daily dose

Celiprolol is already approved in European Union for the following indications:

Approved in European Union as Celiprolol for:

• Hypertension
• Angina pectoris
• Vascular Ehlers-Danlos syndrome

Who Is Running the Clinical Trial?

Acer Therapeutics Inc.

Lead Sponsor

Trials

3

Recruited

220+

Published Research Related to This Trial

In a study of 1145 healthy postmenopausal women over 24 months, raloxifene significantly improved bone mineral density (BMD) and reduced low-density lipoprotein cholesterol (LDL-C) compared to placebo, indicating its potential as a beneficial treatment for osteoporosis and cardiovascular health.

Approximately 50% of women taking raloxifene showed improvements in both BMD and LDL-C, while only 19.1% of the placebo group experienced similar benefits, highlighting the efficacy of raloxifene in promoting bone and heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis. Shah, A., Iversen, P., Mitlak, B.[2020]

The DVO guidelines established in 2003 provide evidence-based strategies for diagnosing and treating osteoporosis, particularly in postmenopausal women and those with glucocorticoid-induced osteoporosis.

Effective treatments include calcium and vitamin D supplementation, as well as antiresorptive therapies like bisphosphonates (alendronate, ibandronate, risedronate) and the SERM raloxifene, which have proven antifracture efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacotherapy of osteoporosis: evidence-based clinical practice]. Fassbender, WJ., Stumpf, UC., Jockenhövel, F.[2007]

In a study of 66 postmenopausal women over 3 years, Tibolone did not increase the volume of uterine myomas, suggesting it is safe for women with these growths.

Tibolone had a notable early effect on uterine blood flow, decreasing the pulsatility index in women without myomas while increasing it in those with myomas, indicating changes in uterine hemodynamics based on myoma presence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long term effects of Tibolone on postmenopausal women with uterine myomas. Gregoriou, O., Konidaris, S., Botsis, D., et al.[2019]

In a study of 1497 women with postmenopausal osteoporosis, over 90% showed good compliance with raloxifene therapy, indicating that patients generally adhered well to their treatment regimen over the 18-month period.

Higher treatment satisfaction and better quality of life were significantly associated with adherence to raloxifene, suggesting that effective osteoporosis management relies on patient cooperation and satisfaction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Raloxifene in clinical practice. Results of the non-interventional study CORAL (COmpliance with RALoxifene)]. Rosa, J., Vanuga, P., Payer, J., et al.[2015]

In a study involving 53 patients with vascular Ehlers-Danlos syndrome, celiprolol significantly reduced the occurrence of arterial events (ruptures or dissections) compared to a control group, with only 20% of the celiprolol group experiencing these events versus 50% in the control group.

The trial, which lasted an average of 47 months and was stopped early due to positive results, suggests that celiprolol could be an effective preventive treatment for this severe condition, although further research is needed to determine its efficacy in patients without the specific collagen mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Ong, KT., Perdu, J., De Backer, J., et al.[2022]

Celiprolol is a unique β-blocker that not only blocks β1 receptors but also partially activates β2 receptors, which may provide additional benefits in treating conditions like vascular type Ehlers-Danlos syndrome.

In a significant study, celiprolol showed promising results in reducing arterial events in patients with vascular Ehlers-Danlos syndrome, leading to the premature termination of the trial due to its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol: A Unique Selective Adrenoceptor Modulator. Nawarskas, JJ., Cheng-Lai, A., Frishman, WH.[2019]

In a study of 40 Swedish patients with vascular Ehlers-Danlos syndrome (vEDS) treated with the beta blocker celiprolol, 65% were able to reach the target dose of 400 mg daily, indicating good tolerability for most patients.

The annual risk of major vascular events was 4.7%, which is comparable to the protective effect observed in the BBEST trial, suggesting that celiprolol may help reduce the risk of serious complications in vEDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome. Baderkhan, H., Wanhainen, A., Stenborg, A., et al.[2021]

In a study involving two children with Ehlers-Danlos syndrome (types VIII and VI), intravenous DDAVP (desmopressin acetate) successfully corrected prolonged bleeding times and provided excellent hemostasis during surgical procedures.

Both patients experienced no postoperative bleeding, suggesting that DDAVP could be a beneficial treatment option for managing bleeding tendencies in patients with EDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DDAVP therapy controls bleeding in Ehlers-Danlos syndrome. Stine, KC., Becton, DL.[2019]

In a study using a mouse model of vascular Ehlers-Danlos syndrome (vEDS), the β-blocker celiprolol significantly improved the biomechanical integrity of the thoracic aorta, potentially reducing the risk of aortic rupture.

In contrast, the angiotensin II receptor antagonist losartan did not show any significant effect on aortic integrity, suggesting that celiprolol may be a more suitable long-term treatment option for patients with vEDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome. Dubacher, N., Münger, J., Gorosabel, MC., et al.[2022]

Raloxifene hydrochloride (RLX) was successfully formulated into a semisolid self-nanoemulsifying system (SSNES) that significantly improved its solubility and tumor penetration, with an optimized globule size of 109.19 nm.

The RLX-loaded SSNES demonstrated strong anti-cancer effects in MCF-7 breast cancer cells by inducing apoptosis through caspase-3 activation and cell cycle arrest, suggesting it could be an effective treatment option for breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimized semisolid self-nanoemulsifying system based on glyceryl behenate: A potential nanoplatform for enhancing antitumor activity of raloxifene hydrochloride in MCF-7 human breast cancer cells. Badr-Eldin, SM., Aldawsari, HM., Ahmed, OAA., et al.[2021]

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