Senicapoc and Dehydrated Stomatocytosis

Dehydrated Hereditary Stomatocytosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04372498
• Other study ID #: IRB-P00034327
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 15, 2021
• Est. completion date: February 1, 2024

Study information

• Verified date: February 2024
• Source: Boston Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: February 1, 2024
• Est. primary completion date: February 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Anemia, Hemolytic, Congenital
• Dehydrated Hereditary Stomatocytosis
• Dehydration

Intervention

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.

Locations

Country	Name	City	State
United States	Boston Children's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Boston Children's Hospital

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	chronic hemolysis biomarkers	Reticulocyte count, bilirubin, LDH, Hemoglobin	6 months
Secondary	Decrease in the frequency and intensity of pain	Splenic, abdominal or other, assessed with Numeric Pain Rating Scale (NPRS).	6 months
Secondary	Improved functional health and well-being	FACT-An QOL questionnaire	6 months
Secondary	Decrease in the frequency and intensity of pain	patient diaries or PDA	optional, 6 months
Secondary	spleen volume	three-dimensional ultrasonography	if available, 6-months