Clinical trial NCT06260891: Zinc Supplementation in Sickle Cell Disease: A Precursor to the Think Zinc for Bones Trial
Official title: Zinc Supplementation in Sickle Cell Disease: A Precursor to the Think Zinc for Bones Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Sickle Cell Disease
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Philadelphia
name: Newark Beth Israel Medical Center
name: University of Pennsylvania
name: Cincinnati Children's Hospital Medical Center (CCHMC)
name: Children's National Research Institute
name: American Society of Hematology
name: Texas Children's
First posted: 2024-02-15
Enrollment: 34
Sex: ALL
Minimum age (years): 15
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a delayed start parallel design where all subjects will have a usual care period, 2 baseline samples 4 weeks apart, followed by a 12 week zinc intervention, with samples at 8 and 12 weeks.
Primary purpose: OTHER

Brief summary: The goal of this short term prospective Phase II study is to compare the effects of two alternate daily doses of zinc (25 and 40 mg/day) in 34 randomly assigned homozygous Sickle Cell Disease (SCD-SS) patients aged 15-35 years old. The main question it aims to answer is: Which biomarkers are most responsive to zinc supplementation, and what is the maximum tolerated zinc dose that induces the desired changes in biomarkers of bone turnover? Participants will be recruited from 7 American Society Hematology Research Collaborative SCD Centers. Eligible SCD subjects will be invited to participate in the 16-week study, involving 2 baseline blood draws 4 weeks apart, followed by a 12-week zinc intervention. The findings from this study will be used to determine the dosage of zinc to be used in a larger, future study on the long term impact of zinc supplementation on bone health in SCD-SS.

Detailed description: The investigators propose a two-arm, double-blinded, Phase II study comparing the effects of two different daily doses of zinc (25 and 40 mg/day) in 34 patients with SCD-SS aged 15-35 years old, randomly assigned to either group. The aim of the study is to determine the maximum tolerated zinc dose that induces desired changes in rates of bone formation and resorption. The findings from this study will function as preliminary data for a future randomized clinical trial and provide a novel characterization of bone marker response to short term zinc supplementation in SCD that has not previously been described in the literature.

SCD is the most prevalent heritable disorder affecting red blood cells worldwide. It is an autosomal recessive genetic condition inherited at birth when a child receives two genes, one from each parent, coding for abnormal hemoglobin. The defective hemoglobin proteins characteristic of SCD give rise to sickle-shaped red blood cells causing serious health complications, including early onset bone morbidity. Over half of young adults with SCD have osteoporosis and are at increased risk for fracture.

Zinc, an essential trace mineral, is crucial for red cell stability, growth and bone metabolism. Zinc deficiency is reported frequently in patients with SCD and has been related to poor growth, increased vaso-occlusive crises and decreased bone density. The etiology of zinc deficiency in SCD is multifactorial, including inadequate dietary intake, increased requirements due to escalations in red cell turnover and elevated urinary losses from renal insufficiency. The investigators hypothesize that bone deficits in individuals with SCD are in part due to zinc deficiency caused by oxidative stress induced hemolysis and elevated bone turnover, and these bone defects can be ameliorated by zinc supplementation.

Studies indicate that zinc improves bone density in thalassemia, a related hemoglobinopathy (Fung, 2013). But thus far, there have not been any randomized prospective studies analyzing the impact of zinc on bone health in individuals with SCD. Although emerging studies have reported that zinc supplementation might improve growth and has the potential for reducing the number and severity of sickle-related painful events, these studies are single center, small and short term. Moreover, there are currently no therapies in SCD focused on bone morbidity, and there is much enthusiasm among individuals with SCD towards participation in a nutritional intervention. A large, multicenter, long term trial of zinc supplementation focused on disease outcomes in SCD is warranted.

In order to determine the optimal tolerated dose of zinc for implementation in a future randomized clinical trial, the investigators have proposed a short term interventional study comparing the effects of two different doses of zinc, 25 vs. 40 mg/day. Subjects will be included if they are between 15 and 35 years of age, have been diagnosed with SCD-SS and are in their steady state of health. The study is a 16-week program, involving 2 baseline blood draws 4 weeks apart, followed by a randomized 12-week zinc intervention. Over the course of the study, the change in measures of bone formation and resorption, will be compared between the usual care period (0 to 4 weeks) and the intervention period (4 to 16 weeks).

Eligibility criteria: Inclusion Criteria:

* Age: ≥ 15.0 to ≤ 35.0 years
* Diagnosis: SCD-SS or SCD-SBeta0 Thalassemia, in steady state (defined as a minimum of 2 weeks days following pain crisis)
* Male or Female (n=17 of each) stratified by age group (15-25 ; 26-35 years)

Exclusion Criteria:

* Taking any supplement containing zinc and unable/willing to stop for 3 months prior to study start
* 25-Hydroxy Vitamin D \< 20 ng/mL
* On chronic transfusion therapy (defined as \>8 Transfusions/year)
* Unable swallow pills or take daily supplement as instructed
* Currently participating in another investigational drug trial
* Prior diagnosis of chronic kidney disease (eGFR \< 30 mL/min/1.73m2)

Primary outcomes:
measure: Biomarker of Bone Formation (PINP)
timeFrame: Total 16 weeks divided into: Usual Care (0 to 4 weeks) vs. Intervention Period (4 to 16 weeks)
measure: Biomarker of Bone Resorption (CTx)
timeFrame: Total 16 weeks divided into: Usual Care (0 to 4 weeks) vs. Intervention Period (4 to 16 weeks)
Secondary outcomes:
measure: Biomarker of Bone Formation (BSAP)
timeFrame: Total 16 weeks divided into: Usual Care (0 to 4 weeks) vs. Intervention Period (4 to 16 weeks)
measure: Biomarker of Bone Resorption (TRAP 5b)
timeFrame: Total 16 weeks divided into: Usual Care (0 to 4 weeks) vs. Intervention Period (4 to 16 weeks)
Other outcomes:
measure: Tolerability of Zinc Supplement
timeFrame: Total 16 weeks divided into: Usual Care (0 to 4 weeks) vs. Intervention Period (4 to 16 weeks)
measure: Adherence to Zinc Supplementation
timeFrame: Total 12 weeks during Intervention Period (4 to 16 weeks)
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
Study officials:
affiliation: University of California, San Francisco
name: Ellen Fung, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fung EB, Kwiatkowski JL, Huang JN, Gildengorin G, King JC, Vichinsky EP. Zinc supplementation improves bone density in patients with thalassemia: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2013 Oct;98(4):960-71. doi: 10.3945/ajcn.112.049221. Epub 2013 Aug 14.