Escalating Doses of VAS-101 in Subjects With Stable Sickle Cell Disease

A Phase 1 Study to Evaluate the Safety and Tolerability of Escalating Doses of VAS-101 in Subjects With Stable Sickle Cell Disease

Background:

Sickle cell disease (SCD) is an inherited blood disorder. The disease affects the ability of red blood cells to carry oxygen. Research has shown that curcumin, a natural compound found in turmeric, can improve the health of red blood cells in people with SCD. But the body cannot absorb curcumin well when it is taken by mouth. Researchers want to know if a skin gel (VAS-101) can help the body better absorb curcumin. VAS-101 contains curcumin, which comes from turmeric.

Objective:

To test VAS-101 in people with stable SCD.

Eligibility:

People aged 18 to 70 years with stable SCD.

Design:

People who want to join the study will be screened with physical exam with blood tests to see if they are eligible. If they qualify, they can enroll in the study.

Participants will have up to 15 clinic visits over about 14 weeks. Some may need to stay overnight in the hospital for up to 2 days to make it easier to collect blood samples after the gel is applied.

For 6 weeks, a special gel called VAS-101 will be put on the forearms in the clinic two times a week. Staff will rub the gel into the skin for at least 30 seconds using a soft toothbrush. The area stays uncovered for at least 10 minutes, then is covered with a bandage or sleeve. After 24 hours, the dressing can be removed and the skin can be washed.

Some visits will include blood tests and other exams. On three visits, a test called near infrared spectroscopy (NIRS) will be done. For this test, probes are placed on the skin to measure blood flow, oxygen levels, and the makeup of skin and muscle. A blood pressure cuff is used to squeeze the arm for up to 5 minutes.

The last clinic visit will happen about 4 weeks after the final gel application....

Study Description:

The overall objective of this study is to assess the clinical safety and tolerability of a patented, bioavailability-enhanced, transdermal application of curcuminoids, VAS-101 / Vasceptor(R) (8.5% curcuminoids transdermal gel), in subjects with stable sickle cell disease (SCD). VAS-101 contains Curcugen(R) as the active ingredient, with concentrations of 2mg in VAS-101 0.05 mL, 4mg in VAS-101 0.1 mL, and 12mg in VAS-101 0.3 mL. Subjects enrolled will receive 0.2 mL of VAS-101 topically twice weekly for two weeks, followed by 0.4 mL twice weekly for two weeks, then 0.6mL twice weekly for two weeks. Throughout the course of the study, subjects will be monitored for signs and symptoms of adverse events. The effect of VAS-101 on laboratory biomarkers of inflammatory activity, red cell metabolism and deformability will also be studied at specific timepoints.

Objectives:

Primary Objective:

To assess the clinical safety and tolerability of escalating doses of a patented, bioavailability-enhanced, transdermal application of curcuminoids, VAS-101 / Vasceptor(R) (8.5% curcuminoids transdermal gel), in adult patients with stable SCD.

Secondary Objectives:

To assess the pharmacokinetics of VAS-101 in SCD and correlate drug exposure to anti-inflammatory and anti-sickling effects at different dose levels.

Tertiary/Exploratory Objectives:

To explore effects of VAS-101 on neutrophil and platelet function, red cell and monocyte metabolism, and muscle physiology.

Endpoints:

Primary Endpoints:

• To evaluate the safety and tolerability of VAS-101 as assessed by:

  --The type, incidence, severity, and relationship to study treatment of AEs and serious adverse events (SAEs) from Baseline to Day 66, including:

• Number of most common treatment related adverse events

• Number of serious adverse events possibly related to treatment

• Number of discontinuations due to AEs from Baseline to Day 66

• Mean change in clinical laboratory test results (e.g., serum chemistry, liver function test, hematology, coagulation) from baseline at each dose level (days 0, 14, 28, 42 and 66).

Secondary Endpoints:

• Percentage of sickled cells, time to 50 percent sickling (t50) and area under sickling curve under hypoxic ex vivo conditions at regular time intervals (days 0, 14, 28, 42 and 66).
• Percentage change in oxygen affinity (p50) at regular time intervals (days 0, 14, 28, 42 and 66).
• Change in intracellular reactive oxidative species (ROS) in RBCs at regular time intervals (days 0, 14, 28, 42 and 66).
• Change in markers of inflammation, adhesion and coagulation activation at regular time intervals (days 0, 14, 28, 42 and 66).

Tertiary/Exploratory Endpoints:

• Proteomic, metabolomic and lipidomic studies to evaluate the effect of VAS-101 on RBCs and monocytes at regular time intervals (days 0, 14, 28, 42 and 66).
• Evaluate effect of VAS-101 on RBC band 3 tyrosine phosphorylation at regular time intervals (days 0, 14, 28, 42 and 66).
• Assessment of muscle physiology, tissue oxygenation and blood flow using near infrared spectroscopy (NIRS) methodologies at regular time intervals (days 0, 42 and 66).
• Evaluate effect of VAS-101 on neutrophil activation and neutrophil extracellular trap (NET) formation at baseline and regular time intervals (days 0, 14, 28, 42 and 66).
• Studies of extracellular vesicles (EVs) at regular time intervals (days 0, 14, 28, 42 and 66).

• INCLUSION CRITERIA:

Subjects will enroll onto the study and undergo screening. Subjects who do not meet any of the following criteria during screening will not receive the study intervention but will be counted toward study accrual. Screen failures may be rescreened at a later time. In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
• Age between 18-70 years. Adults over 70 years of age will be excluded from this study due to an increased risk of more severe disease and higher prevalence of multiple comobodities.
• Unequivocal diagnosis of SCD (HbSS, HbSC, HbSbeta+ or HbSbeta^0) confirmed by hemoglobin electrophoresis performed on patients at least 60 days after a blood transfusion if previously transfused.
• No transfusion in the 60 days prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
• Serum aspartate aminotransferase (AST) <= 1.5 x Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis) and alanine aminotransferase (ALT) <=1.5 x ULN.
• Hemoglobin >= 7 g/dL
• Serum creatinine <=1.25 x ULN. If serum creatinine is >1.25 x ULN, then glomerular filtration rate (based on creatinine) must be >=60 mL/min.
• If on hydroxyurea, participant must have been on stable dose of hydroxyurea (defined as a stable dose for at least 90 days and inclusive of dose modifications for hematological toxicity per PI discretion) prior to signing consent.
• If on L-glutamine and/or crizanlizumab, participant must have been on a stable dose for ast least 90 days prior to signing consent.
• Agree to abstain from taking any other products/supplements containing turmeric or curcumin until all study visits have been completed (oral, topical, etc.)
• For women of reproductive potential, have a negative serum pregnancy test during the screening period. Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (i.e., who have not menstruated at all for at least the preceding 1 year prior to signing informed consent unrelated to hormonal contraception).
• Women of reproductive potential be abstinent as part of their usual lifestyle, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 28 days following the last dose of study treatment. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine or subdermal contraceptive implants, and barrier methods.
• Be willing to comply with all study procedures for the duration of the study.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Vaso-occlusive crisis requiring parenteral treatment within 14 days of signing consent.

• Three or more vaso-occlusive crises in the 12 months prior to screening that resulted in receiving treatment in an urgent care, outpatient infusion center/day-clinic, emergency department or inpatient setting.

• Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:

  • Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mmHg or diastolic BP >90 mmHg) refractory to medical management.
  • History of recent (within 24 weeks prior to signing consent) decompensated congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
  • Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.
  • History of drug-induced cholestatic hepatitis.
  • Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (e.g., clinically significant impaired left ventricular ejection fraction), hepatic (e.g., fibrosis, cirrhosis), or pancreatic (e.g., diabetes) dysfunction.
  • Positive test for hepatitis B surface antigen or hepatitis C virus (HCV) antibody (Ab) with signs of active hepatitis B or C virus infection. If the subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment.
  • Active infection requiring any use of systemic antimicrobial agents (parenteral or oral) or Grade >=3 in severity (per National Cancer Institute Common Terminology Criteria for Adverse Events) within 4 weeks prior to signing consent.
  • Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary.
  • History of any primary malignancy, with the exception of: curatively treated nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years.
  • Current or recent history of psychiatric disorder that, in the opinion of the Investigator or Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures.
  • Have had a prior bone marrow or stem cell transplant.

• Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo.

• Taking nitroglycerin, or any other nitrate-enhancing drug.

• Have exposure to any investigational drug, device, or invasive procedure within 12 weeks prior to signing consent. All non-investigational invasive procedures within 12 weeks of signing consent may be considered as a potential exclusion criteria per the PI's discretion.

• Currently pregnant or breastfeeding.

• Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 90 days prior to signing consent.

• Have a history of allergy to turmeric, curcuminoids, or formulations thereof.