THRV-1268 for Atrial Fibrillation

Overseen By Alexandre Brkovic, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Thryv Therapeutics, Inc.

Must not be taking: Immunosuppressants, St. John's wort

Disqualifiers: Pregnancy, Hypertension, Heart disease, others

Compensation: Varies

Number of Visits: 8

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-center, randomized, double-blind, placebo-controlled study to be conducted in 2 parts: single ascending dose (SAD) incorporating a food effect arm and multiple ascending dose (MAD). Potential participants for each part will undergo screening procedures within 28 days of enrollment.

Do I need to stop taking my current medications for the trial?

Yes, you will need to stop taking any prescription drugs (except for hormonal contraceptives or hormone replacement therapy) 28 days before the first study drug administration. Over-the-counter or nutritional supplements should be stopped 7 days before the first study drug administration.

What data supports the idea that THRV-1268 for Atrial Fibrillation is an effective treatment?

The available research does not provide any data supporting the effectiveness of THRV-1268 for Atrial Fibrillation. The studies mentioned focus on treatments for hemophilia A, a different condition, and do not include information about THRV-1268 or its use for Atrial Fibrillation. ^{1 2 3 4 5}

What safety data exists for THRV-1268 in treating atrial fibrillation?

The provided research does not contain specific safety data for THRV-1268 or its other names like Placebo, Control, or Dummy Treatment in the context of atrial fibrillation. The studies focus on other treatments and conditions related to atrial fibrillation, such as anticoagulants, apixaban, COVID-19 vaccines, and angiotensin-receptor blockers, but do not mention THRV-1268. ^{6 7 8 9 10}

Is the drug THRV-1268 a promising treatment for atrial fibrillation?

The research suggests that drugs like angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can help prevent atrial fibrillation. They have shown significant effects in reducing the chances of AF, especially in patients already using other treatments like amiodarone. If THRV-1268 works similarly to these drugs, it could be a promising treatment for atrial fibrillation. ^{10 11 12 13 14}

Eligibility Criteria

This trial is for individuals with atrial fibrillation, a heart condition causing irregular heartbeat. Participants will be screened within 28 days before joining the study to ensure they meet specific health requirements.

Inclusion Criteria

Stated willingness to comply with all study procedures and availability for the duration of the study

I am using birth control, am postmenopausal, or have been surgically sterilized.

I have not smoked or have quit smoking for at least 6 months.

Exclusion Criteria

I am currently breastfeeding.

Abnormal ECG findings

Pregnant females

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Single Ascending Dose (SAD)

Participants receive a single oral dose of THRV-1268 or placebo, with a food effect arm integrated into one cohort

1 day

1 visit (in-person)

Multiple Ascending Dose (MAD)

Participants receive THRV-1268 or placebo daily from Day 1 to Day 7

1 week

7 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Placebo
• THRV-1268

Trial Overview The study tests THRV-1268 against a placebo in two parts: one where participants take a single dose and another where they take multiple doses. The effects of food on the drug are also being studied.

Participant Groups

Group I: Single Ascending Dose (SAD) THRV-1268 Experimental Treatment 1 Intervention

5 dosing cohorts will receive a single oral dose of THRV-1268. The highest dose of THRV-1268 to be administered is 500 mg.

Group II: Multiple Ascending Dose (MAD) THRV-1268 Experimental Treatment 1 Intervention

3 dosing cohorts will receive THRV-1268 in the morning on Day 1 to Day 7.

Group III: Food Effect THRV-1268 Experimental Treatment 1 Intervention

food effect will be integrated into one of the SAD cohorts as a single dose, two-period with at least a 7-day washout, crossover cohort.

Group IV: Single Ascending Dose (SAD) Placebo Placebo Group 1 Intervention

5 dosing cohorts will receive a single oral dose of placebo.

Group V: Food Effect Placebo Placebo Group 1 Intervention

Food effect will be integrated into one of the SAD cohorts as a single dose, two-period with at least a 7-day washout, crossover cohort.

Group VI: Multiple Ascending Dose (MAD) Placebo Placebo Group 1 Intervention

3 dosing cohorts will receive placebo in the morning from Day 1 to Day 7.

Who Is Running the Clinical Trial?

Thryv Therapeutics, Inc.

Lead Sponsor

Trials

3

Recruited

150+

Findings from Research

BAY 81-8973 demonstrated effective bleed prevention and treatment in previously untreated or minimally treated patients with severe hemophilia A, with a median annualized bleeding rate of 0.0 within 48 hours after prophylaxis infusion among patients without inhibitors.

While the study observed a higher than expected rate of inhibitors (39.5% high titer), immune tolerance induction was successful in 50% of patients who underwent treatment, indicating that BAY 81-8973 maintains a favorable benefit-risk profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial. Ljung, R., Chan, AKC., Glosli, H., et al.[2023]

In a study involving 212 patients with severe hemophilia A, full-length sucrose-formulated recombinant factor VIII (rFVIII-FS) demonstrated high efficacy, successfully treating 85.4% of bleeding episodes with one or two infusions.

The long-term safety profile of rFVIII-FS was confirmed, with a low incidence of inhibitor formation (8.0% in previously untreated patients), supporting its use in clinical practice for up to 24 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: experience in the standard clinical setting. Musso, R., Santagostino, E., Faradji, A., et al.[2018]

BAY 94-9027, an extended-half-life recombinant factor VIII product, demonstrated a significantly higher pharmacokinetic profile compared to rFVIIIFc, with a higher area under the curve (AUClast) indicating better drug exposure in patients with hemophilia A.

The study, involving 18 patients aged 18-65, found no adverse events, suggesting that BAY 94-9027 is safe for use, and it also showed a longer time to reach FVIII threshold levels, which may benefit patients needing sustained factor levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct comparison of two extended-half-life recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A. Shah, A., Solms, A., Wiegmann, S., et al.[2023]

The Phase 3 A-LONG study showed that rFVIIIFc is highly effective for treating acute bleeding episodes in severe hemophilia A, with 98% of episodes resolving after one or two infusions.

Among subjects receiving prophylactic treatment, a significant number (60% in individualized prophylaxis) did not experience target joint bleeds, highlighting the potential of rFVIIIFc to prevent bleeding complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A. Shapiro, AD., Mahlangu, JN., Perry, D., et al.[2017]

A study involving 67 laboratories across 25 countries found that most clinical labs accurately measured the activity of N8-GP (turoctocog alfa pegol) and rAHF (Advate®) using their routine FVIII activity assays, ensuring effective monitoring of hemophilia A treatment.

However, three specific silica-based aPTT reagents significantly underestimated N8-GP levels, recovering only 40%-83% of the target concentration, highlighting the need for careful selection of reagents in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A field study evaluating the activity of N8-GP in spiked plasma samples at clinical haemostasis laboratories. Tiefenbacher, S., Clausen, WHO., Hansen, M., et al.[2021]

In a network meta-analysis of 39 studies involving 27,766 patients, continuous vitamin K antagonist (C-VKA) was found to significantly reduce thromboembolic events and major bleeding complications compared to interrupted vitamin K antagonist (I-VKA) in patients undergoing radiofrequency catheter ablation for atrial fibrillation.

Rivaroxaban was identified as the most effective and safest non-vitamin K oral anticoagulant, showing a lower risk of thromboembolism compared to I-VKA, making it a strong alternative to C-VKA for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Network meta-analysis of efficacy and safety of competitive oral anticoagulants in patients undergoing radiofrequency catheter ablation of atrial fibrillation. Li, PJ., Xiao, J., Yang, Q., et al.[2018]

Patients with atrial fibrillation (AF) undergoing transfemoral aortic valve replacement (TAVR) experienced significantly higher rates of early safety issues and all-cause mortality compared to those in sinus rhythm, with 20.6% of AF patients facing mortality or stroke within 12 months.

Among AF patients, those treated with apixaban had a significantly lower rate of early safety events compared to those on vitamin K antagonists (VKAs), suggesting that apixaban may be a safer anticoagulant option post-TAVR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement. Seeger, J., Gonska, B., Rodewald, C., et al.[2018]

A systematic analysis of 6226 reports of atrial fibrillation (AF) related to COVID-19 vaccines showed that AF is a rare adverse event, accounting for only 0.3% of all vaccine-related reports in the European pharmacovigilance database from 2020 to November 2022.

Most AF cases were reported in adults over 65 years old, with 35% requiring hospitalization and 10% being life-threatening, although the majority of AF events were of short duration (median = 24 hours).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COVID-19 Vaccines and Atrial Fibrillation: Analysis of the Post-Marketing Pharmacovigilance European Database. Ruggiero, R., Donniacuo, M., Mascolo, A., et al.[2023]

A systematic review of 11 randomized clinical trials involving 56,308 patients found that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduced the relative risk of developing atrial fibrillation (AF) by 28%.

The greatest benefit was observed in patients with heart failure, where the risk of AF was reduced by 44%, while no significant reduction was noted in patients with hypertension, except for those with left ventricular hypertrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. Healey, JS., Baranchuk, A., Crystal, E., et al.[2023]

Candesartan significantly reduces the atrial fibrillatory rate in patients with high baseline rates (>420 fibrillations/min), indicating its potential anti-arrhythmic effects in atrial fibrillation.

Despite reducing the fibrillatory rate, candesartan did not improve the success of cardioversion outcomes, suggesting that lower fibrillatory rates (<360 fpm) are more critical for successful cardioversion rather than the drug's effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fibrillatory rate response to candesartan in persistent atrial fibrillation. Bollmann, A., Tveit, A., Husser, D., et al.[2021]

In a study of 160 patients with recent atrial fibrillation, oral doses of flecainide, amiodarone, and propafenone were all significantly more effective than placebo in converting patients to sinus rhythm within 24 hours, with conversion rates of 87.5%, 85%, and 85% respectively compared to only 17.5% for placebo.

Flecainide and propafenone showed quicker conversion rates within 3 hours (57.5% and 45% respectively), while amiodarone was more effective between 6 and 24 hours, indicating that different antiarrhythmic drugs may have varying onset times for effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological conversion of recent atrial fibrillation: a randomized, placebo-controlled study of three antiarrhythmic drugs. Balla, I., Petrela, E., Kondili, A.[2013]

A systematic review of 21 trials involving 91,381 patients found that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduced the incidence of atrial fibrillation (AF) by 25%.

The effectiveness of ACEIs/ARBs was particularly notable in patients with hypertension, chronic heart failure, and those already diagnosed with AF, showing a relative risk reduction of 24% for primary prevention and 27% for secondary prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the incidence of atrial fibrillation: a meta-analysis. Huang, G., Xu, JB., Liu, JX., et al.[2011]

The study found no strong evidence supporting the use of ACE inhibitors or ARBs as effective treatments for preventing or managing atrial fibrillation (AF).

Despite the lack of solid evidence for their antiarrhythmic effects, ACE inhibitors and ARBs may still be beneficial for patients with recurrent AF, especially if they have other conditions like hypertension, heart failure, or diabetes, due to their low side effect profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of the renin angiotensin system blocking in the management of atrial fibrillation. Soran, H., Ziglam, H., Al-Najjar, M., et al.[2017]

A meta-analysis of 26 randomized controlled trials found that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) significantly reduce the risk of developing atrial fibrillation (AF), with an overall odds ratio of 0.65, indicating a strong preventive effect.

The preventive effects were particularly pronounced for recurrent AF (odds ratio of 0.45) compared to new-onset AF (odds ratio of 0.80), and were most effective in patients already treated with amiodarone, suggesting a synergistic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Zhang, Y., Zhang, P., Mu, Y., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: experience in the standard clinical setting. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

Direct comparison of two extended-half-life recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A. [2017]

5. England pubmed.ncbi.nlm.nih.gov

A field study evaluating the activity of N8-GP in spiked plasma samples at clinical haemostasis laboratories. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Network meta-analysis of efficacy and safety of competitive oral anticoagulants in patients undergoing radiofrequency catheter ablation of atrial fibrillation. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

COVID-19 Vaccines and Atrial Fibrillation: Analysis of the Post-Marketing Pharmacovigilance European Database. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Fibrillatory rate response to candesartan in persistent atrial fibrillation. [2021]

11. Turkey pubmed.ncbi.nlm.nih.gov

Pharmacological conversion of recent atrial fibrillation: a randomized, placebo-controlled study of three antiarrhythmic drugs. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the incidence of atrial fibrillation: a meta-analysis. [2011]

13. England pubmed.ncbi.nlm.nih.gov

The role of the renin angiotensin system blocking in the management of atrial fibrillation. [2017]

14. United States pubmed.ncbi.nlm.nih.gov

The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. [2022]