Angiotensin-converting Enzyme Inhibitors and Early Sickle Cell Renal Disease in Children (MADREPIEC)

Interest of Angiotensin-converting Enzyme Inhibitors on Early Sickle Cell Renal Disease in Children. A Randomized, Double-blind Trial Enalapril vs Placebo.

Patients with sickle cell anaemia may develop renal disease. In fact, renal disease occurred in 40% of adults patients (macroalbuminuria) with evolution to end-stage renal disease for half of them. Microalbuminuria is an early and sensitive marker of glomerular damage. It appears during the first decade and occurred in 20 to 25% of infants (2 to 18 years). Physiopathology of renal scarring is not well understood actually. Renal scarring might be due to glomerular hyperfiltration and vascular and endothelial damage. Angiotensin-converting enzyme inhibitors (ACE) were studied and used in diabetic nephropathy. In a study on 26 sickle cell adults, albuminuria was reduced about 50% by ACE compared to placebo after six months treatment. It might be interesting studying ACE efficacy in sickle cell children with microalbuminuria because renal disease is directly related to sickle cell and is not influenced by other cardiovascular risk factors like in adult patients.

We hypothesized to have a successful ACE treatment in more than 40% of cases after a nine months treatment period. A success is defined as a 50% reduction of the albuminuria/creatinuria ratio.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Placebo; Drug: Enalapril

Detailed Description

This is a multicenter study. In order to include 72 patients we should pre-include 400 patients.

They will be included in the study after signing the protocol consent. For final inclusion in the study, two albuminuria/creatinuria ratio should be over or equal to 3mg/mmol. If so, inclusion will be done and patient will be randomized (placebo/enalapril) by CLEANWEB software. A blood sample will be done.

Treatment tolerance will be check up at day 7 (blood sample for renal tolerance and clinical examination), month 1(clinical examination), month 3(clinical examination), month 6(clinical examination), and month 9 (clinical examination). Treatment efficacy will be evaluated by albuminuria/creatinuria ratio at month 1, month 3, month 6, and month 9. Physiopathology of ACE efficacy will be studied at first day and month 9 by dosage of ICAM-1 and VCAM-1.

Treatment plain posology (0.5mg/kg/day) will be progressively obtained on a three months period, beginning at 0.2mg/kg/day.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75012
    • Trousseau Hospital, Nephro-pediatric unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Sickle cell disease (SS, SC, Sb thalassemia, SD Punjab)
• Affiliation to French Health benefits
• Signed informed consent
• Albuminemia / Creatinemia >= 3 mg / mmol (on 2 samples)

Exclusion Criteria:

• Albuminemia / Creatinemia > 100 mg / mmol
• Hypersensibility to enalapril
• Angio-oedemas due to a previous treatment by ACE
• idiopathic or hereditary angio-oedemas
• cerebral echo-doppler
• treatment by lithium digoxine
• treatment by other ACE
• congenital galactosemia
• Pregnancy

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
Placebo Comparator: 2	Drug: Placebo; Glucose; Other Names: Glucose
Experimental: 1; Enalapril	Drug: Enalapril; during 1 month : 0,2 mg/kg/day; then during 2 months (if no adverse event): 0,35 mg/kg/day; and then during 6 months (if no adverse event): 0,5 mg/kg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of successful treatment of each arm	Successful treatment is defined by a reduction by half of the albuminuria/ creatinuria ratio (mg / mmol).	at 9 months of treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Measure of albuminuria/ creatinuria ratio	at 1, 3 and 6 month of treatment.
Dosage of circulating forms of cell adhesion molecules ICAM-1 and VCAM-1	at the first day and at 9 months of treatment.

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Tim ULINSKI, PH, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Sasongko TH, Nagalla S. Angiotensin-converting enzyme (ACE) inhibitors for proteinuria and microalbuminuria in people with sickle cell disease. Cochrane Database Syst Rev. 2021 Dec 21;12(12):CD009191. doi: 10.1002/14651858.CD009191.pub4.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: March 29, 2010
• First Submitted That Met QC Criteria: March 29, 2010
• First Posted (Estimate): March 30, 2010

Study Record Updates

• Last Update Posted (Estimate): July 26, 2012
• Last Update Submitted That Met QC Criteria: July 25, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Renal disease; Angiotensin-converting enzyme inhibitors (ACE); Microalbuminemia
• Additional Relevant MeSH Terms: Urologic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Kidney Diseases; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalapril
• Other Study ID Numbers: P071222; AOM08052 (Other Identifier: Assistance Publique - Hôpitaux de Paris)