Back to results

Senicapoc and Dehydrated Stomatocytosis

Primary Purpose

Dehydrated Hereditary Stomatocytosis

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Senicapoc (synonyms: ICA-17043; 2,2-bis-(4-fluorophenyl)-2-phenylacetamide)

About this trial

This is an interventional treatment trial for Dehydrated Hereditary Stomatocytosis

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients carrying KCNN4 mutations in V282M as described in 1981 by Snyder et al and Sauberman et al. and characterized molecularly by Andolfo et al. in 2015 , and other patients with V282 mutations with demonstrated in-vitro sensitivity to senicapoc, will be eligible to participate in this study if they meet all the following criteria:
1. Have a diagnosis of dehydrated stomatocytosis with a molecularly confirmed mutation in KCNN4.
2. Are at least 21 years of age.
3. Have hematological manifestations of dehydrated stomatocytosis such as elevated MCHC, compensated or uncompensated chronic hemolysis, with reticulocytosis. For enrollment, 3/5 of the following baseline value must meet enrollment criteria:
  Reference Range Enrollment criterion MCHC 32-36 mg/dL > 36 mg/dL Reticulocyte count (absolute) 0.25-0.90 x 103/µL > 0.200 x 103/µL Bilirubin, Indirect 0.2-1.2 mg/dL > 1.5 mg/dL Haptoglobin. 43-212 mg/dL < normal LDH 100-220 U/L > normal
4. Personally dated and signed informed consent detailing all the pertinent aspects of the study.
5. Willingness to adhere to study visit schedule, treatment plan, blood draws and laboratory tests and other study procedures.

Exclusion Criteria:

Patient will be excluded from the study if they meet any of the following criteria:
RBC transfusion in the prior 90 days.
Recent (within the past 30 days) hospitalization for major surgical procedure, infection requiring IV treatment, or significant bleeding complications.
Recent (within 2 weeks) diagnosis of cerebrovascular accident of transient ischemic attack.
Hepatic dysfunction serum alanine transferase or GGT values > 3 times the upper limit of normal, total serum bilirubin values > 20 mg/dL
Renal disease (defined as serum creatinine greater than 1.2 mg/dL, or a requirement for chronic dialysis).
Severe symptomatic anemia defined as a Hct value < 18%.
Any other severe acute or chronic medical condition or laboratory alteration that may increase the risks associated with participation to this study and/or administration of senicapoc, based on the clinical judgement of the principal investigator.
Any condition that may interfere with the study subject's ability to adhere to study schedule, or comply with blood drawing requirements, such as inadequate venous access.
Pregnancy or breastfeeding for female subjects.
Concurrent use of illicit drugs and/or alcohol dependence, as determined by the principal investigator.

Sites / Locations

Boston Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

This is a pivotal trial in members of the same family carrying the V282M nutation in the Gardos channel (KCNN4) and other patients with V282 mutations with demonstrated in-vitro sensitivity to senicapoc. These mutations lead to hyperactivation of the channel and red cell dehydration. Up to 6 patients are eligible to enroll in this study, which will assess effectiveness based on individual changes of primary endpoints over individually established baselines.

Outcomes

Primary Outcome Measures

chronic hemolysis biomarkers

Reticulocyte count, bilirubin, LDH, Hemoglobin

Secondary Outcome Measures

Decrease in the frequency and intensity of pain

Splenic, abdominal or other, assessed with Numeric Pain Rating Scale (NPRS).

Improved functional health and well-being

FACT-An QOL questionnaire

Decrease in the frequency and intensity of pain

patient diaries or PDA

spleen volume

three-dimensional ultrasonography

Full Information

NCT ID

NCT04372498

First Posted

April 30, 2020

Last Updated

April 20, 2023

Sponsor

Boston Children's Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04372498

Brief Title

Senicapoc and Dehydrated Stomatocytosis

Official Title

An Explananatory, Proof-of-concept Study of Senicapoc in Patients With Familial Dehydrated Stomatocytosis Caused by the V282M Mutation in the Gardos (KCNN4) Channel

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 15, 2021 (Actual)

Primary Completion Date

December 15, 2023 (Anticipated)

Study Completion Date

March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Boston Children's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Dehydrated stomatocytosis is a genetic disorder characterized by chronic hemolysis, variable anemia and erythrocyte dehydration. Causative mutations have been identified in either the Gardos (KCNN4) channel or the mechanosensitive channel PIEZO1. Senicapoc is a selective blocker of the Gardos channel that has been extensively studied in sickle cell disease and shown to be safe with limited side-effects. However, senicapoc did not meet the designated clinical endpoints in a pivotal phase 3 trial. The present study is an explanatory, proof-of-concept study of Senicapoc administered once daily in patients with familial dehydrated stomatocytosis caused by autosomal dominant V282 mutations in the Gardos (KCNN4) channel.

Detailed Description

The proposed study is an explanatory, proof-of-concept study of Senicapoc administered once daily in patients with familial dehydrated stomatocytosis caused by the autosomal dominant V282 mutation in the Gardos (KCNN4) channel. The study population will include up to 6 members of the same family, all carrying the V282M mutation, and other V282 mutations with demonstrated in-vitro sensitivity to senicapoc, meeting study criteria for inclusion and exclusion. Patients will begin the study with a loading dose of 20 mg/day for 4 days followed by a dose of 10 mg once daily for the first 4 weeks of study. After 4 weeks at the initial dose, patients will be escalated to higher doses (in 3 steps of 10 mg every 4 weeks) to a maximal dose of 40 mg once daily. Patients who demonstrate response in the primary endpoints at the end of the efficacy study, and who have not been permanently discontinued due to Senicapoc-attributed serious adverse events (SAE), will be eligible for a 12-month study extension at the dose determined to be effective in the treatment efficacy study. Patients who meet inclusion criteria will be enrolled at visit 0, and if available, will be provided with the appropriated instrument to record daily pain scores and other QOL indicators. Treatment will begin at Visit 1, which will follow visit 0 after 2-3 weeks. After an effective dose and tolerated has been established in the dose escalation period, patients will be seen every two weeks until they reach 24 weeks of treatment. Patients will be seen for a potential maximum of 19 visits in the treatment efficacy phase of the study, with additional phone contacts after the first week of treatment and within a week from each dose escalation. At the end of the efficacy portion of the study, patients will be eligible to participate in a one-year optional open-label extension, provided that they have not been permanently discontinued from the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Dehydrated Hereditary Stomatocytosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Senicapoc (synonyms: ICA-17043; 2,2-bis-(4-fluorophenyl)-2-phenylacetamide)

Intervention Description

This study is conducted as open label, with each patient's response determined with an adaptive Bayesian model based on historical and baseline values for the primary endpoints of the trial. 3 monthly dose escalation steps will assess the efficacy of senicapoc in a dose range (10-40 mg/day) which has been used in prior trials for other indications.

Primary Outcome Measure Information:

Title

chronic hemolysis biomarkers

Description

Reticulocyte count, bilirubin, LDH, Hemoglobin

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Decrease in the frequency and intensity of pain

Description

Splenic, abdominal or other, assessed with Numeric Pain Rating Scale (NPRS).

Time Frame

6 months

Title

Improved functional health and well-being

Description

FACT-An QOL questionnaire

Time Frame

6 months

Title

Decrease in the frequency and intensity of pain

Description

patient diaries or PDA

Time Frame

optional, 6 months

Title

spleen volume

Description

three-dimensional ultrasonography

Time Frame

if available, 6-months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients carrying KCNN4 mutations in V282M as described in 1981 by Snyder et al and Sauberman et al. and characterized molecularly by Andolfo et al. in 2015 , and other patients with V282 mutations with demonstrated in-vitro sensitivity to senicapoc, will be eligible to participate in this study if they meet all the following criteria: Have a diagnosis of dehydrated stomatocytosis with a molecularly confirmed mutation in KCNN4. Are at least 21 years of age. Have hematological manifestations of dehydrated stomatocytosis such as elevated MCHC, compensated or uncompensated chronic hemolysis, with reticulocytosis. For enrollment, 3/5 of the following baseline value must meet enrollment criteria: Reference Range Enrollment criterion MCHC 32-36 mg/dL > 36 mg/dL Reticulocyte count (absolute) 0.25-0.90 x 103/µL > 0.200 x 103/µL Bilirubin, Indirect 0.2-1.2 mg/dL > 1.5 mg/dL Haptoglobin. 43-212 mg/dL < normal LDH 100-220 U/L > normal Personally dated and signed informed consent detailing all the pertinent aspects of the study. Willingness to adhere to study visit schedule, treatment plan, blood draws and laboratory tests and other study procedures. Exclusion Criteria: Patient will be excluded from the study if they meet any of the following criteria: RBC transfusion in the prior 90 days. Recent (within the past 30 days) hospitalization for major surgical procedure, infection requiring IV treatment, or significant bleeding complications. Recent (within 2 weeks) diagnosis of cerebrovascular accident of transient ischemic attack. Hepatic dysfunction serum alanine transferase or GGT values > 3 times the upper limit of normal, total serum bilirubin values > 20 mg/dL Renal disease (defined as serum creatinine greater than 1.2 mg/dL, or a requirement for chronic dialysis). Severe symptomatic anemia defined as a Hct value < 18%. Any other severe acute or chronic medical condition or laboratory alteration that may increase the risks associated with participation to this study and/or administration of senicapoc, based on the clinical judgement of the principal investigator. Any condition that may interfere with the study subject's ability to adhere to study schedule, or comply with blood drawing requirements, such as inadequate venous access. Pregnancy or breastfeeding for female subjects. Concurrent use of illicit drugs and/or alcohol dependence, as determined by the principal investigator.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Carlo Brugnara, MD

Phone

6173556610

Carlo.Brugnara@childrens.harvard.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Carlo Brugnara, MD

Organizational Affiliation

Boston Children's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Boston Children's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115-5724

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Carlo Brugnara

Phone

617-448-2534

carlo.brugnara@childrens.harvard.edu

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

26178367

Citation

Andolfo I, Russo R, Manna F, Shmukler BE, Gambale A, Vitiello G, De Rosa G, Brugnara C, Alper SL, Snyder LM, Iolascon A. Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol. 2015 Oct;90(10):921-6. doi: 10.1002/ajh.24117.

Results Reference

background

PubMed Identifier

7259992

Citation

Snyder LM, Sauberman N, Condara H, Dolan J, Jacobs J, Szymanski I, Fortier NL. Red cell membrane response to hydrogen peroxide-sensitivity in hereditary xerocytosis and in other abnormal red cells. Br J Haematol. 1981 Jul;48(3):435-44. doi: 10.1111/j.1365-2141.1981.tb02735.x.

Results Reference

background

PubMed Identifier

7285342

Citation

Sauberman N, Fairbanks G, Lutz HU, Fortier NL, Snyder LM. Altered red blood cell surface area in hereditary xerocytosis. Clin Chim Acta. 1981 Aug 10;114(2-3):149-61. doi: 10.1016/0009-8981(81)90388-0.

Results Reference

background

Learn more about this trial

Senicapoc and Dehydrated Stomatocytosis

We'll reach out to this number within 24 hrs