Magnesium Supplements In The Treatment Of Pseudoxanthoma Elasticum (PXE)
Magnesium Supplements In The Treatment Of Pseudoxanthoma Elasticum (PXE)
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.
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.
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