Phase 2 Study of Montelukast for the Treatment of Sickle Cell Anemia

Phase 2 Study of Montelukast for the Treatment of Sickle Cell Anemia (Also Known as the Montelukast Trial in Sickle Cell Anemia)

In this feasibility trial, the investigators will compare participants treated with montelukast and hydroxyurea to those treated with placebo and hydroxyurea for a total of 8 weeks.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Anemia (HbSS, or HbSβ-thalassemia0)
• Intervention / Treatment: Drug: Montelukast added to Hydroxyurea; Drug: Placebo added to Hydroxyurea

Detailed Description

The primary hypothesis for this trial is that montelukast adds efficacy to hydroxyurea therapy for improving vaso-occlusion when compared to hydroxyurea alone. The following specific aims will be tested in adolescents and adults with sickle cell disease (SCD):

Aim 1. To determine whether montelukast versus placebo added to hydroxyurea will improve markers of vaso-occlusion-associated tissue injury in adolescents and adults with sickle cell disease.

Aim 2. To evaluate physiologic effects of montelukast versus placebo added to hydroxyurea in adolescents and adults with sickle cell disease.

Subaim 2A. To determine if montelukast versus placebo added to hydroxyurea will improve lung function in adolescents and adults with sickle cell disease.

Subaim 2B. To determine if montelukast versus placebo added to hydroxyurea will improve forearm microvascular blood flow in adolescents and adults with sickle cell disease, respectively.

Funding Source - FDA OOPD

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9000
      • Vanderbilt University Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 66 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1)Diagnosis of HbSS, or HbSβ-thalassemia0, confirmed by hemoglobin analysis
• 2)Males and females age 16 years to 70 years old
• 3)Greater than 2 episodes of pain in the last 12 months
• 4)On a stable dose of hydroxyurea for at least 2 months and a stable hemoglobin

Exclusion Criteria:

1. Judged not likely to be study compliant by his/her hematologist
2. History of adverse reaction to montelukast or any of the components of montelukast
3. Have used medications known to interact with montelukast such as rifampin, phenobarbital, and gemfibrozil within 4 weeks of enrollment
4. Currently being treated with a leukotriene antagonist (montelukast or zileuton) or have used montelukast/zileuton within the last 60 days
5. Chronic blood transfusion therapy defined as regularly scheduled transfusions.
6. Hemoglobin A greater than15% on hemoglobin analysis
7. Individuals with a current physician diagnosis of asthma (within last 12 months) or requires continuous supplemental oxygen, or predicted or current use of asthma medications (inhaled corticosteroids, but participants taking bronchodilators will be allowed to participate).
8. Current participation in another therapeutic trial for SCD
9. Known current pregnancy
10. Known history of HIV
11. Serum creatinine greater than 3 times the site's upper limit of normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Montelukast added to Hydroxyurea; Oral montelukast therapy taken daily for eight weeks with current hydroxyurea regiment	Drug: Montelukast added to Hydroxyurea
Placebo Comparator: Placebo added to Hydroxyurea; Oral placebo taken daily for eight weeks with current hydroxyurea regiment	Drug: Placebo added to Hydroxyurea

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Soluble Vascular Cell Adhesion Molecule-1 (sVCAM)	The primary outcome measure is based on a 30% reduction, which would be ~106 ng/ml reduction. The study was designed with 25 in each group in order to explore all three aims and potential confounders. However, if the investigators are not able to accrue 25 subjects in each arm, the investigators would still be able to detect a 30% difference in sVCAM with 17 subjects in each group. The 95% confidence interval for detecting a 30% difference is between 204 ng/ml and 290 ng/ml (or an 18-42% reduction in sVCAM). Importantly, the lower limit of the 95% confidence interval (18%) is still a clinically relevant reduction in sVCAM. Thus, if the investigators detect a 30% or larger difference in sVCAM in this study, the investigators will be assured that, based on the 95% confidence interval, these data are clinically important.	baseline to eight weeks

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: Medical College of Wisconsin; Versiti
• Investigators: Principal Investigator: Michael R. DeBaun, MD, MPH, Vanderbilt University Medical Center; Principal Investigator: Joshua Field, MD, MS, Medical College of Wisconsin

Publications and helpful links

General Publications

• Field JJ, Kassim A, Brandow A, Embury SH, Matsui N, Wilkerson K, Bryant V, Zhang L, Simpson P, DeBaun MR. Phase 2 trial of montelukast for prevention of pain in sickle cell disease. Blood Adv. 2020 Mar 24;4(6):1159-1165. doi: 10.1182/bloodadvances.2019001165.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: October 8, 2013
• First Submitted That Met QC Criteria: October 8, 2013
• First Posted (Estimate): October 10, 2013

Study Record Updates

• Last Update Posted (Actual): March 26, 2019
• Last Update Submitted That Met QC Criteria: March 7, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia; Anemia, Sickle Cell; Thalassemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Antisickling Agents; Montelukast; Hydroxyurea
• Other Study ID Numbers: R01FD004117 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices)
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication
• IPD Sharing Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)