Senicapoc and Dehydrated Stomatocytosis

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

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.

Study Overview

• Status: Completed
• Conditions: Dehydrated Hereditary Stomatocytosis
• Intervention / Treatment: Drug: Senicapoc (synonyms: ICA-17043; 2,2-bis-(4-fluorophenyl)-2-phenylacetamide)

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Carlo Brugnara, MD; Phone Number: 6173556610; Email: Carlo.Brugnara@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115-5724
      • Boston Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; 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.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
chronic hemolysis biomarkers	Reticulocyte count, bilirubin, LDH, Hemoglobin	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decrease in the frequency and intensity of pain	Splenic, abdominal or other, assessed with Numeric Pain Rating Scale (NPRS).	6 months
Improved functional health and well-being	FACT-An QOL questionnaire	6 months
Decrease in the frequency and intensity of pain	patient diaries or PDA	optional, 6 months
spleen volume	three-dimensional ultrasonography	if available, 6-months

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Principal Investigator: Carlo Brugnara, MD, Boston Children's Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2021
• Primary Completion (Actual): February 1, 2024
• Study Completion (Actual): February 1, 2024

Study Registration Dates

• First Submitted: April 30, 2020
• First Submitted That Met QC Criteria: April 30, 2020
• First Posted (Actual): May 4, 2020

Study Record Updates

• Last Update Posted (Actual): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic; Water-Electrolyte Imbalance; Dehydration; Anemia, Hemolytic, Congenital
• Other Study ID Numbers: IRB-P00034327

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No