Effect of Oral Cimetidine in the Protoporphyrias

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) result from genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. The objective of this study is to determine the efficacy and safety of oral cimetidine administration for treatment of the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. Funding Source- FDA OOPD

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. EPP and XLP, collectively called the protoporphyrias, result in the accumulation of the light-sensitive molecule protoporphyrin IX initially in the bone marrow during hemoglobin synthesis and secondarily in erythrocytes, plasma, and the liver. In addition to photosensitivity, protoporphyria can also result in anemia, gallstones, and liver failure. No therapy has been demonstrated to reduce protoporphyrin levels or prevent the potentially life-threatening complications of EPP. Cimetidine has gained attention as a possible treatment for human porphyrias because of a potential off-target effect of inhibition of delta-aminolevulinate synthase (ALAS), the first enzyme of heme biosynthesis. This inhibition was first described in vitro; however, case reports of benefit in EPP have been anecdotal and uncontrolled. Therefore, the objective of this study is to determine the efficacy and safety of oral cimetidine administration in the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. If the results are positive, this would be the first study providing quality evidence for an agent acting as a disease-modifying therapy for EPP. The study is also attractive because it repurposes an already approved drug with few side effects to treat a rare human disease. The study design is a prospective, blinded, randomized, 2x2 cross-over design comparing cimetidine to placebo in patients with protoporphyria. Eligible protoporphyria patients will be randomized with equal allocation to one of two treatment sequences that will be administered over two 3-month study periods. Randomization will be stratified by site and permuted block randomization will be used to prevent chronological bias. Patients randomized to sequence 1 will receive placebo during period 1 and cimetidine during period 2. Patients randomized to sequence 2 will receive cimetidine during period 1 and placebo during period 2. Between periods, to eliminate any carry-over effects from the treatment administered in period 1, a wash-out period of 3 months will occur in which all patients receive neither cimetidine nor placebo. Three months was selected for each study period and for the wash-out period because of the rapid decline in protoporphyrin in red cells over the lifespan of the red cell (120 days), as well as to account for the time frame needed to measure light sensitivity in EPP.

The study design is a multicenter, prospective, randomized, double-blind, placebo-controlled, crossover trial of oral cimetidine 800mg twice daily versus placebo

Patient-reported quality of life as measured by Patient-Reported Outcomes Measurement Information System-57 (PROMIS-57) scale [0-100, where 100 is the best quality of life]

Inclusion Criteria: Prior enrollment or co-enrollment in the Longitudinal Study of the Porphyrias (PC Study 7201) with a confirmed diagnosis of EPP or XLP Male or female age ≥15 years at screening Characteristic history of non-blistering cutaneous photosensitivity Willing and capable of giving informed consent and following procedures described in the protocol Exclusion Criteria: Participants not willing to expose themselves to light to the point of prodromal symptoms at least weekly History of liver or bone marrow transplant or clinically significant liver dysfunction as determined by the Investigator Known or suspected allergy or intolerance to cimetidine Use of any other experimental therapy in the past 3 months at screening Use of cimetidine within the past 3 months at screening Individuals with elevations of porphyrins in plasma or erythrocytes due to other diseases (i.e., secondary porphyrinemia) such as liver and bone marrow diseases Patients with any clinically significant comorbid conditions, which in the opinion of the Investigator, precludes participation Treatment with any drugs or supplements (Appendix 1) that in the opinion of the Investigator can interfere with subject safety or the objectives of the study The participant either does not have a smartphone or is not willing to use his/her smartphone for the study Women who are pregnant, breastfeeding, or actively planning to become pregnant Individuals with moderate to severe renal insufficiency

Individual participant data that underlie the results reported in the published article, as well as the study protocol and statistical analysis plan, may be shared, after de-identification (text, tables, figures, and appendices), if meeting the time frame and access criteria listed below.

With whom: Researchers who provide a methodologically sound proposal that is approved by the study investigators For what type of analysis: To achieve the aims of the approved proposal. By what mechanisms will the data be available: Proposals should be directed to adickey@mgh.harvard.edu . To gain access, data requestors will need to sign a data access agreement.