Clinical trial NCT00142051: Inhaled Nitric Oxide for Pediatric Painful Sickle Crisis
Official title: Inhaled Nitric Oxide for Pediatric Painful Sickle Crisis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Sickle Cell Disease
Keywords: sickle cell disease
pain crisis
vaso-occlusive crisis
nitric oxide
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: FDA Office of Orphan Products Development
First posted: 2005-09-02
Enrollment: 18
Sex: ALL
Minimum age (years): 9
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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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Primary outcomes:
measure: Difference in change in mean pain score (visual analog scale) after 16 hours of treatment between patients treated with INO and placebo.
timeFrame: every 4 hrs x duration of hospitalization
Secondary outcomes:
measure: Secondary outcome measures to evaluate efficacy
timeFrame: Duration of hospitalization, followup
measure: Longitudinal analyses of change in VAS pain score over 16 hours.
timeFrame: every 4 hrs, duration of hospitalization
measure: Change in pain score using a 5 point descriptive scale and a 5 point relief scale.
timeFrame: every 4 hours duration of hospitalization
measure: Time to pain score less than 5 cm for 2 consecutive VAS pain assessments 4 hours apart and not using parenteral narcotics.
timeFrame: every 4 hrs, duration of hospitalization
measure: Use of pain medication: cumulative dose of parenteral narcotic pain medications.
timeFrame: While patient on parenteral narcotic
measure: Duration of hospitalization.
timeFrame: Time of discharge
measure: Inflammatory markers/mediators.
timeFrame: 0, 16 and q 24 hrs during hospitalization
measure: Secondary outcome measures to evaluate safety are:
timeFrame: 4, 8, 16, 24 hrs methb, constant NO2, 02 during inhalation
measure: Maximum concentration of methemoglobin.
timeFrame: 0, 4, 8, 16, 24 hrs
measure: Maximum concentration of nitrogen dioxide (NO2) delivered.
timeFrame: continuous over 24 hrs of inhalaiton
measure: Minimum percent oxygen saturation of hemoglobin (by pulse oximetry).
timeFrame: continuous over 24 hrs of inhalation then every 4 hrs for duration of hospitalization
measure: Maximum and minimum vital signs: pulse, respiratory rate, blood pressure.
timeFrame: every 4 hrs during hospitalization
Other outcomes:
Locations:
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Debra Weiner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.