Hereditary Hemorrhagic Telangiectasia (HHT), Osler Weber Rendu Disease
Conditions
Keywords
Arteriovenous malformations, ATV-1601, HarmonyHHT, Harmony-HHT, HarmonyHHTStudy, Vascular Diseases, Bleeding disorders, Hematologic disorders, Disorders, Telangiectasias, Hereditary hemorrhagic, Hemorrhagic disorders, Cardiovascular diseases, Vascular malformations, HHT
Brief summary
This is a 2-part study evaluating ATV-1601 in participants with moderate to severe HHT. Part 1 is a randomized, double-blind, placebo-controlled study evaluating 3 dosing regimens of ATV-1601. Patients completing Part 1 may participate in the Part 2 open-label extension to receive ATV-1601.
Detailed description
Part 1: This is a Phase 1/2 proof-of-concept, double-blind, multicenter, placebo-controlled study to evaluate the safety, pharmacokinetics and efficacy of 3 oral dosing regimens of ATV-1601. Participants who meet eligibility requirements will be randomized in a double-blind manner to one of 3 doses of ATV-1601 or placebo. Participants will receive double-blind study treatment for a 16-week period. Part 2: Eligible participants who complete Part 1 may enroll in an open-label extension study to receive up to 2 years of additional treatment. All participants in the open-label extension will receive ATV-1601. Once the recommended Phase 2 dose (RP2D) is determined based on Part 1, all participants in Part 2 will have the option to switch to the RP2D.
Interventions
DRUGATV-1601
Administered orally, daily
DRUGPlacebo
Administered orally, daily
Sponsors
Atavistik Bio, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants will be randomized to one of 3 doses of ATV-1601 or placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Ability to provide informed consent prior to any study-specific procedures * Confirmed diagnosis of hereditary hemorrhagic telangiectasia (HHT) based on Curaçao criteria * Moderate to severe HHT with an ESS ≥ 4 * Anemia at Screening and/or requirement for at least 1 red-cell unit (RUE) in the previous 6 months * Adequate hematologic, renal, and hepatic function per protocol-defined laboratory criteria * Use highly effective contraception during the study and for a protocol-defined period after last dose
Exclusion criteria
* Clinically significant abnormalities of glucose metabolism including diagnosed Type 1 or uncontrolled Type 2 diabetes * Chronic cardiac disease, or cardiac rhythm abnormalities * History of significant cardiovascular, hepatic, renal, or hematologic disease not related to HHT that may confound study results * Use of prohibited concomitant medications within a protocol-defined washout period prior to first dose (including strong CYP modulators and certain herbal supplements) * Recent (within 6 weeks) major surgery or local ablative procedures, or procedures on nasal telangiectasias * Prior AKT inhibitor * Pregnant or breastfeeding women Additional Criteria for Open-Label Extension: * Participants must complete the double-blind treatment period (Part 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Safety and tolerability | 16 weeks | Number and severity of treatment-emergent adverse events (TEAEs) and study drug-related TEAEs |
| Part 2: Safety and tolerability | 24 months | Type, incidence, severity, timing, seriousness and relatedness of AEs and laboratory abnormalities |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Change in Epistaxis duration | 16 weeks | 28-day total duration compared to baseline |
| Part 1: Epistaxis frequency | 16 weeks | 28-day frequency of nosebleeds compared to baseline |
| Part 1: Epistaxis intensity | 16 weeks | 28-day average epistaxis intensity (6-point scale) of nosebleeds compared to baseline |
| Part 1: Intensity-weighted epistaxis duration | 16 weeks | 28-day intensity-weighted duration of nosebleeds |
| Part 1: Epistaxis Severity Score (ESS) | 16 weeks | The Epistaxis Severity Score (ESS) is a validated 6-question instrument with scores ranging from 0 to 10, where higher scores indicate more severe epistaxis symptoms. |
| Part 1: Change in Hemoglobin | 16 weeks | Hemoglobin levels compared to baseline |
| Part 1: Change in Parenteral iron use | 16 weeks | Amount of parenteral iron administered compared to 16-weeks prior to treatment initiation |
| Part 1: Change in Blood transfusion requirements | 16 Weeks | Amount of packed red blood cell (PRBC) transfusions and rate of transfusion independence compared to 16-weeks prior to treatment initiation |
| Part 1: Pharmacokinetics - Maximum observed concentration (Cmax) | 16 Weeks | Maximum plasma concentration |
| Part 1: Pharmacokinetics - Area under the concentration-time curve over the dosing interval (AUCtau) | 16 Weeks | Systemic exposure of ATV-1601 over the dosing interval |
| Part 1: Pharmacokinetics - Area under the concentration-time curve extrapolated to infinity (AUCinf) | 16 Weeks | Total systemic exposure of ATV-1601 extrapolated to infinite time |
| Part 1: Pharmacokinetics - Time to maximum concentration (Tmax) | 16 Weeks | Time to reach maximum plasma concentration |
| Part 1: Pharmacokinetics - minimum concentration (Cmin) | 16 Weeks | Pre-dose trough plasma concentration |
| Part 1: Pharmacokinetics - Half-life (t½) | 16 Weeks | Time required for plasma concentration to decrease by half |
| Part 2: Epistaxis duration | Up to 2 years | 28-day total duration every 4 weeks |
| Part 2: Epistaxis frequency | Up to 2 years | Total number of nosebleeds every 4 weeks |
| Part 2: Epistaxis Severity Score (ESS) | At 12 weeks and every 12 weeks thereafter up to study completion | Severity of nosebleeds using a score of 0-10 automatically calculated based on responses to 6 questions. |
| Part 2: Change in Hemoglobin | Monthly during Part 2 | Hemoglobin levels compared to baseline |
| Part 2: Parenteral iron use | At 12 weeks and every 12 weeks thereafter up to study completion | Total amount of parenteral iron infused (mg) compared to baseline (12 weeks prior to treatment initiation |
| Part 2: Blood transfusion requirements | At 12 weeks and every 12 weeks thereafter during part 2 | Total number of packed red blood cell (PRBC) transfusions (units) compared to baseline |
| Part 2: Transfusion independence | At 12 weeks and every 12 weeks thereafter during part 2 | Proportion of participants who do not require PRBC transfusions |
Countries
United States
Contacts
CONTACTStudy Director
Outcome results
None listed