Magnesium Supplements In The Treatment Of Pseudoxanthoma Elasticum (PXE)

• ClinicalTrials.gov Identifier: NCT01525875
• Recruitment Status: Completed
• First Posted: February 3, 2012
• Results First Posted: April 25, 2019
• Last Update Posted: March 10, 2021
• Sponsor: Mark Lebwohl
• Information provided by (Responsible Party): Mark Lebwohl, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

The purpose of this study is to evaluate the effectiveness of magnesium oxide supplements on the reversal of calcium deposits in the skin, and the yellow bumps and folds of skin in subjects with pseudoxanthoma elasticum (PXE). Magnesium oxide is a dietary supplement that has been shown in some research to reduce these calcium deposits. This study consists of two parts. The first part is a year-long, double-blind, placebo-controlled study. Part two is an open-label, year-long study. In Part 1, qualified subjects will be randomized to receive either magnesium oxide supplements or placebo, in a 1:1 ratio for the first 12 months. The starting dose will be 1000 mg daily, and depending on tolerability, doses may be decreased. Baseline evaluations will be comprised of: blood tests; clinical evaluations; skin biopsy; eye examination; bone density test; and photography of skin lesions. Subjects will be evaluated at week 2, week 6, month 3, and then every 3 months during the first year. Upon completion of the first year, barring any safety concerns, all subjects will be administered magnesium oxide supplements for up to one additional year. Subjects will undergo the same evaluations/ procedures every 3 months. We hypothesize that the magnesium oxide will cause a reduction in calcifications in the subject's soft tissue/skin. Funding Source - FDA OOPD.

Condition or disease	Intervention/treatment	Phase
Pseudoxanthoma Elasticum	Drug: Magnesium Oxide; Drug: Placebo	Phase 2

Detailed Description:

Pseudoxanthoma elasticum (PXE) is a systemic connective tissue disorder involving elastic fiber calcification and fragmentation with major clinical manifestations occurring in the cutaneous, ocular and cardiovascular systems.

Calcification of the elastic fibers leads to cracks in Bruch's membrane, an elastic tissue-containing membrane that separates the vascular choroid from the retinal pigment epithelium. These are known as angioid streaks and may be the only sign of the disease for years. Retinal hemorrhage and loss of vision are common. Calcification of the internal elastic lamina of arteries results in gastrointestinal bleeding, sometimes fatal in nature. Accelerated heart disease is an additional complication.

Cutaneous manifestations are characterized by the presence of yellow papules in a cobblestone pattern or plaques resembling "plucked chicken-skin" in flexural regions. Redundant folds of skin may develop in more advanced cases. The most frequent sites of cutaneous involvement include the neck, axillae, inguinal region, antecubital and popliteal fossae and the periumbilical area. Skin lesions provide an easy way of grading degree of calcification of elastic tissue.

A clinical study of 80 subjects with a variety of cutaneous soft tissue mineralization disorders had the affected areas injected locally with magnesium sulfate while also receiving oral magnesium lactate for 4 to 6 months. About 75% of these subjects showed a significant decrease or complete disappearance of calcification.

More recently, a knockout mouse model for PXE has linked a reversal in calcification to a diet high in magnesium. Mice were placed on diets that were either high or low in phosphate, high or low in magnesium, or on a controlled diet. The mice placed on the high magnesium diet did not show any evidence of connective tissue mineralization, while those on the other diets did show mineralization as characterized by calcification of the connective tissue capsule surrounding the vibrissae.

Based on this information and the research linking increased magnesium levels to decreased calcification, we plan to supplement the diets of PXE patients with magnesium oxide in order to show a reduction in elastic fiber calcification in the skin and to slow the progression of the disease.

Randomized subjects will be instructed to take study drug (active or placebo) for 12 months, then all subjects will receive active study drug for the following 12 months.

When ingested through foods, magnesium has not demonstrated any adverse effects. When obtained through supplements, however, excessive magnesium intake has been known to result in diarrhea as well as other gastrointestinal effects such as nausea, and abdominal cramping. Large pharmacological doses of magnesium have been associated with more serious side effects, such as metabolic alkalosis and hypokalemia with the repeated daily ingestion of 30g of magnesium oxide. Hypermagnesemia may result with excessive magnesium supplement ingestion, however, it has rarely been reported in individuals with normal renal function.

Study data will be analyzed using the Wilcoxon Rank Sum Test to compare changes in physician global assessment of skin lesions, evaluation of target lesions and assessment of biopsies between treatment and placebo groups. Assuming a negligible placebo response, we believe power analyses can be performed on our primary measure in 40 completed subjects as proposed in this study. Analyses will be based on intent-to-treat, with the last observation carried forward. Patients who withdraw for safety, lack of efficacy, and generally those without other documentation will in the absence of the requested 'final-visit evaluation' be assigned the highest (worst) score. A finding of significance based on the intent-to-treat analysis would be supplemented with an analysis of patients completing the trial without any protocol deviations.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Magnesium Supplements In The Treatment Of Pseudoxanthoma Elasticum (PXE)
• Study Start Date: August 2012
• Actual Primary Completion Date: March 2015
• Actual Study Completion Date: March 2015

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Magnesium oxide; Part 1: 1000 mg elemental magnesium (given as one 800 mg capsule of magnesium oxide two times daily). Part 2: 1500 mg elemental magnesium (given as two 500 mg capsules of magnesium oxide in the morning and three 500 mg capsules of magnesium oxide in the evening).	Drug: Magnesium Oxide; Part 1: 1000 mg elemental magnesium (given as one 800 mg capsule of magnesium oxide two times daily). Part 2: 1500 mg elemental magnesium (given as two 500 mg capsules of magnesium oxide in the morning and three 500 mg capsules of magnesium oxide in the evening).; Other Name: magnesium oxide supplement
Placebo Comparator: Placebo; Part 1: 1000 mg (one 500 mg capsule two times daily) of placebo.	Drug: Placebo; 1000 mg (one 500 mg capsule two times daily) of placebo.; Other Name: silica and/or cellulose

Outcome Measures

Primary Outcome Measures :

1. Von Kossa Staining Per Unit Area of Dermis [ Time Frame: up to 2 years ]
   A blinded dermatopathologist graded skin biopsies on the density of Von Kossa staining, assessed changes in the amount of calcification of elastic fibers by assessing von Kossa staining per unit area of dermis

Secondary Outcome Measures :

1. Number of Participants With a 1-point Decrease of Target Lesions [ Time Frame: up to 2 years ]
   Changes in skin skin lesions observed through investigator evaluations and clinical photographs. The number of patients with a 1-point decrease of target lesions
2. LogMar [ Time Frame: 2 years ]
   Rate of disease progression - Changes observed through ophthalmologic examinations. (+) a decrease in this score indicates improvement of the disease (-) an increase in this score indicates worsening of the disease. LogMAR: logarithm of the minimum angle of resolution. The LogMAR scale converts the geometric sequence of a traditional chart to a linear scale. It measures visual acuity loss: positive values indicate vision loss, while negative values denote normal or better visual acuity.
3. VAS - Visual Acuity Score [ Time Frame: 2 years ]
   Rate of disease progression observed through ophthalmologic examinations.(+) an increase in this score indicates improvement of the disease (-) a decrease in this score indicates worsening of the disease. VAS ranges from 10 to 200, with higher score indicating poorer visual acuity.
4. Central Retinal Thickness [ Time Frame: 2 years ]
   Rate of disease progression observed through ophthalmologic examinations. (+) a decrease in this scores indicates improvement of the disease; (-) an increase in this scores indicates improvement of the disease.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female subject at least 18 years of age
• If female, the subject is not pregnant or nursing
• If female of child bearing potential, the subject has a negative urine pregnancy test at the first visit, and agrees to use an approved method of contraception (hormonal contraceptives [birth control pills, implants [Norplant] or injections [DepoProvera]); intrauterine device (IUD); two forms of barrier methods [condoms and diaphragm]; or abstinence (no sexual activity) throughout the entire study
• Biopsy confirmed diagnosis of pseudoxanthoma elasticum (documenting some calcification of elastic fibers)
• Subject has a clinical disease severity grade of at least "1" (Poorly defined, barely visible macules) at screening.
• Normal kidney function tests

Exclusion Criteria:

• Any subject who is pregnant or becomes pregnant during the study
• Subjects with a serum creatinine greater than 1.6 mg/dL
• Subjects with hypermagnesemia, hypokalemia, or idiopathic hypercalciuria
• Subjects with kidney disease or renal tubular defects (eg. Fanconi's syndrome), or on dialysis
• Subjects with hypothyroidism or hypoparathyroidism or primary hyperparathyroidism
• Subjects with acute gout
• Subjects with malabsorption, or osteomalacia
• Subjects on diuretics, magnesium containing antacids, or anabolic steroids
• Subjects with Cushing's syndrome
• Subjects receiving lithium and those with significant psychiatric disorders that would likely interfere with participation in this study
• Subjects taking anti-seizures medications and anti-arrhythmics medications
• Subjects on tetracycline or metronidazole and ace inhibitors
• Subjects taking cyclosporine or calcineurin inhibitors

Contacts and Locations

Locations

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

Sponsors and Collaborators

Mark Lebwohl

Investigators

• Principal Investigator: Mark Lebwohl, MD; Icahn School of Medicine at Mount Sinai

More Information

Publications:

Lebwohl M, Neldner K, Pope FM, De Paepe A, Christiano AM, Boyd CD, Uitto J, McKusick VA. Classification of pseudoxanthoma elasticum: report of a consensus conference. J Am Acad Dermatol. 1994 Jan;30(1):103-7. doi: 10.1016/s0190-9622(08)81894-4. No abstract available.

Neldner KH. Pseudoxanthoma elasticum. Clin Dermatol. 1988 Jan-Mar;6(1):1-159. doi: 10.1016/0738-081x(88)90003-x. No abstract available.

Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol. 1982 Mar-Apr;26(5):235-46. doi: 10.1016/0039-6257(82)90158-8.

Renie WA, Pyeritz RE, Combs J, Fine SL. Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity. Am J Med Genet. 1984 Oct;19(2):235-44. doi: 10.1002/ajmg.1320190205.

Martinez-Hernandez A, Huffer WE, Neldner K, Gordon S, Reeve EB. Resolution and repair of elastic tissue calcification in pseudoxanthoma elasticum. Arch Pathol Lab Med. 1978 Jun;102(6):303-5.

Sapadin AN, Lebwohl MG, Teich SA, Phelps RG, DiCostanzo D, Cohen SR. Periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks--apparent regression with hemodialysis. J Am Acad Dermatol. 1998 Aug;39(2 Pt 2):338-44. doi: 10.1016/s0190-9622(98)70385-8.

Sherer DW, Singer G, Uribarri J, Phelps RG, Sapadin AN, Freund KB, Yanuzzi L, Fuchs W, Lebwohl M. Oral phosphate binders in the treatment of pseudoxanthoma elasticum. J Am Acad Dermatol. 2005 Oct;53(4):610-5. doi: 10.1016/j.jaad.2004.11.066.

Blum R, Phelps R, Fuchs W, Lebwohl M. Oral Phosphate Binders in the Treatment of Pseudoxanthoma Elasticum. 64th Annual Meeting American Academy of Dermatology March 3-7, 2006, San Francisco, CA. Manuscript in press J Amer Acad Dermatol 2011

Steidl L, Ditmar R. Treatment of soft tissue calcifications with magnesium. Acta Univ Palacki Olomuc Fac Med. 1991;130:273-87.

LaRusso J, Li Q, Jiang Q, Uitto J. Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-)). J Invest Dermatol. 2009 Jun;129(6):1388-94. doi: 10.1038/jid.2008.391. Epub 2009 Jan 1.

Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J. 1984 Jul;108(1):188-93. doi: 10.1016/0002-8703(84)90572-6. No abstract available.

Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu heart study. Am J Clin Nutr. 1987 Feb;45(2):469-75. doi: 10.1093/ajcn/45.2.469.

Paolisso G, Passariello N, Pizza G, Marrazzo G, Giunta R, Sgambato S, Varricchio M, D'Onofrio F. Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects. Acta Endocrinol (Copenh). 1989 Jul;121(1):16-20. doi: 10.1530/acta.0.1210016.

Rude RK, Singer FR. Magnesium deficiency and excess. Annu Rev Med. 1981;32:245-59. doi: 10.1146/annurev.me.32.020181.001333. No abstract available.

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington (DC): National Academies Press (US); 1997. Available from http://www.ncbi.nlm.nih.gov/books/NBK109825/

Bashir Y, Sneddon JF, Staunton HA, Haywood GA, Simpson IA, McKenna WJ, Camm AJ. Effects of long-term oral magnesium chloride replacement in congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1993 Nov 15;72(15):1156-62. doi: 10.1016/0002-9149(93)90986-m.

Urakabe S, Nakata K, Ando A, Orita Y, Abe H. Hypokalemia and metabolic alkalosis resulting from overuse of magnesium oxide. Jpn Circ J. 1975 Oct;39(10):1135-7. doi: 10.1253/jcj.39.1135.

• Responsible Party: Mark Lebwohl, Principal Investigator, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01525875
• Other Study ID Numbers: GCO 09-1157; FD-R-0003903 ( Other Grant/Funding Number: FDA OOPD )
• First Posted: February 3, 2012
• Results First Posted: April 25, 2019
• Last Update Posted: March 10, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Mark Lebwohl, Icahn School of Medicine at Mount Sinai:

pseudoxanthoma elasticum; calcification

Additional relevant MeSH terms:

Pseudoxanthoma Elasticum; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin Diseases; Magnesium Oxide; Antacids; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents