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

• ClinicalTrials.gov Identifier: NCT01960413
• Recruitment Status: Completed
• First Posted: October 10, 2013
• Results First Posted: March 26, 2019
• Last Update Posted: March 26, 2019
• Sponsor: Vanderbilt University Medical Center
• Collaborators: Medical College of Wisconsin; Versiti
• Information provided by (Responsible Party): Michael DeBaun, Vanderbilt University Medical Center

Tracking Information

• First Submitted Date: October 8, 2013
• First Posted Date: October 10, 2013
• Results First Submitted Date: March 7, 2019
• Results First Posted Date: March 26, 2019
• Last Update Posted Date: March 26, 2019
• Study Start Date: November 2013
• Actual Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 7, 2019)

Change in Soluble Vascular Cell Adhesion Molecule-1 (sVCAM) [ Time Frame: baseline to eight weeks ]

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.

Original Primary Outcome Measures (submitted: October 8, 2013)

Improvement in soluble vascular cell adhesion molecule-1 (sVCAM) [ Time Frame: Eight weeks ]

Our 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 we are not able to accrue 25 subjects in each arm, we 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, in our opinion, a clinically relevant reduction in sVCAM. Thus, if we detect a 30% or larger difference in sVCAM in this study, we will be assured that, based on the 95% confidence interval, these data are clinically important.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 2 Study of Montelukast for the Treatment of Sickle Cell Anemia
• Official Title: Phase 2 Study of Montelukast for the Treatment of Sickle Cell Anemia (Also Known as the Montelukast Trial in Sickle Cell Anemia)
• Brief Summary: 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.

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Sickle Cell Anemia (HbSS, or HbSβ-thalassemia0)

Intervention

• Drug: Montelukast added to Hydroxyurea
• Drug: Placebo added to Hydroxyurea

Study Arms

• Experimental: Montelukast added to Hydroxyurea
  Oral montelukast therapy taken daily for eight weeks with current hydroxyurea regiment
  Intervention: Drug: Montelukast added to Hydroxyurea
• Placebo Comparator: Placebo added to Hydroxyurea
  Oral placebo taken daily for eight weeks with current hydroxyurea regiment
  Intervention: Drug: Placebo added to Hydroxyurea

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 1, 2018): 46
• Original Estimated Enrollment (submitted: October 8, 2013): 63
• Actual Study Completion Date: March 2018
• Actual Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years to 70 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01960413
• Other Study ID Numbers: R01FD004117( U.S. FDA Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

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

• Current Responsible Party: Michael DeBaun, Vanderbilt University Medical Center
• Original Responsible Party: Michael DeBaun, Vanderbilt University, Professor of Pediatrics and Medicine, JC Peterson Endowed Chair in Pediatrics, Vice Chair for Clinical Research in Pediatrics, Director, Vanderbilt-Meharry-Matthew Walker Center for Excellence in Sickle Cell Disease
• Current Study Sponsor: Vanderbilt University Medical Center
• Original Study Sponsor: Vanderbilt University

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

• PRS Account: Vanderbilt University Medical Center
• Verification Date: March 2019