Inhaled Nitric Oxide for Pediatric Painful Sickle Crisis

Randomized, double blind placebo controlled clinical trial to evaluate effectiveness and safety of inhaled nitric oxide for the treatment of sickle cell painful crisis in pediatric patients with sickle cell disease.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: nitric oxide; Drug: oxygen

Detailed Description

The specific aim of this study is to evaluate the clinical effectiveness of inhaled nitric oxide (INO) for the treatment of acute vaso-occlusive pain crisis in pediatric patients with sickle cell disease. Nitric oxide (NO) deficiency is known to be central to the pathophysiology of vaso-occlusion. The aim is unchanged from the original application. The study is a randomized, double blind, placebo controlled, clinical trial with eligible patients randomized to receive either NO (with 21% O2 final concentration) for 16 hrs with 8 hr wean (80 ppm 0-8 hrs, 40 ppm 9-16 hrs, 20 ppm 17-20 hrs, 10 ppm 21-24 hrs) or placebo (21% O2 alone) for 24 hrs. The null hypothesis is that there is no difference in change in mean pain score after 16 hours between patients treated with NO and placebo. The primary outcome measure of the study remains the difference in mean change in pain scores between groups as assessed using a 10 cm visual analogue pain scale (VAS). Secondary outcome measures also remain the same. The study is a next step to our completed FDA Orphan Product Development Grant funded study (FD-R-001686) that evaluated safety and efficacy of NO used for 4 hrs for treatment of vaso-occlusive crisis in pediatric patients with sickle cell disease.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years to 22 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hemoglobin SS, Hemoglobin Sß0thal or Hemoglobin SC documented by prior hemoglobin electrophoresis.
2. Age 9 years or greater, age 22 years or less; pediatric age range, old enough to comply with mask and give reliable pain assessment score.
3. Acute pain crisis defined as pain in abdomen, back and/or extremities that cannot be explained by a diagnosis other than sickle cell disease.
4. Initial pain score at least 6 cm; to optimize the likelihood of observing a significant difference in change in pain score between INO treated and placebo groups. Based on data from our previous study, it is anticipated that patients will have an average pre-inhalation pain score of approximately 8 cm.

Exclusion Criteria:

1. > 24 pain crises in the last 12 months. Patients with very frequent pain crisis may have biologic and/or psychosocial pathophysiology that differs from those with fewer pain crises.
2. Pain crisis treated at a medical facility within the last 12 hours.
3. Use of investigational drugs other than hydroxyurea within the last 30 days.
4. Significant respiratory compromise (initial SaO2 < 90%) and/or patients likely to have acute chest syndrome (chest pain and infiltrate) will be eliminated.
5. Clinically significant acute or chronic cardiac dysfunction.
6. Acute priapism.
7. New focal neurologic symptoms.
8. Concurrent documented or suspected bacterial or parvovirus infection.
9. Temperature > 38.4ºC. These patients may have concomitant infection.
10. Transfusion within 30 days or chronic transfusion therapy.
11. Pregnant female
12. Cigarette smoker > 1/2 ppd.

13. Allergy to morphine

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Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; inhaled NO	Drug: nitric oxide; 80 ppm 8 hrs, 40 ppm 8 hrs, 20 ppm 4 hrs, 10 ppm 4 hrs
Placebo Comparator: 2; room air inhalation	Drug: oxygen; oxygen fi02 21% (room air)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in change in mean pain score (visual analog scale) after 16 hours of treatment between patients treated with INO and placebo.	every 4 hrs x duration of hospitalization

Secondary Outcome Measures

Outcome Measure	Time Frame
Secondary outcome measures to evaluate efficacy	Duration of hospitalization, followup
Longitudinal analyses of change in VAS pain score over 16 hours.	every 4 hrs, duration of hospitalization
Change in pain score using a 5 point descriptive scale and a 5 point relief scale.	every 4 hours duration of hospitalization
Time to pain score less than 5 cm for 2 consecutive VAS pain assessments 4 hours apart and not using parenteral narcotics.	every 4 hrs, duration of hospitalization
Use of pain medication: cumulative dose of parenteral narcotic pain medications.	While patient on parenteral narcotic
Duration of hospitalization.	Time of discharge
Inflammatory markers/mediators.	0, 16 and q 24 hrs during hospitalization
Secondary outcome measures to evaluate safety are:	4, 8, 16, 24 hrs methb, constant NO2, 02 during inhalation
Maximum concentration of methemoglobin.	0, 4, 8, 16, 24 hrs
Maximum concentration of nitrogen dioxide (NO2) delivered.	continuous over 24 hrs of inhalaiton
Minimum percent oxygen saturation of hemoglobin (by pulse oximetry).	continuous over 24 hrs of inhalation then every 4 hrs for duration of hospitalization
Maximum and minimum vital signs: pulse, respiratory rate, blood pressure.	every 4 hrs during hospitalization

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: FDA Office of Orphan Products Development
• Investigators: Principal Investigator: Debra Weiner, MD, PhD, Boston Children's Hospital

Publications and helpful links

General Publications

• Gladwin MT, Kato GJ, Weiner D, Onyekwere OC, Dampier C, Hsu L, Hagar RW, Howard T, Nuss R, Okam MM, Tremonti CK, Berman B, Villella A, Krishnamurti L, Lanzkron S, Castro O, Gordeuk VR, Coles WA, Peters-Lawrence M, Nichols J, Hall MK, Hildesheim M, Blackwelder WC, Baldassarre J, Casella JF; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011 Mar 2;305(9):893-902. doi: 10.1001/jama.2011.235.
• Weiner DL, Hibberd PL, Betit P, Cooper AB, Botelho CA, Brugnara C. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA. 2003 Mar 5;289(9):1136-42. doi: 10.1001/jama.289.9.1136. Erratum In: JAMA. 2004 Aug 25;292(8):925.

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: August 31, 2005
• First Submitted That Met QC Criteria: August 31, 2005
• First Posted (Estimate): September 2, 2005

Study Record Updates

• Last Update Posted (Estimate): February 23, 2023
• Last Update Submitted That Met QC Criteria: February 14, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: vaso-occlusive crisis; sickle cell disease; nitric oxide; pain crisis
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: 04-09-119; FD-R-002560-01 (Other Grant/Funding Number: FDA)